WO2022161377A1 - A phamaceutical composition comprising a glucopyranosyl derivative - Google Patents
A phamaceutical composition comprising a glucopyranosyl derivative Download PDFInfo
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- WO2022161377A1 WO2022161377A1 PCT/CN2022/073911 CN2022073911W WO2022161377A1 WO 2022161377 A1 WO2022161377 A1 WO 2022161377A1 CN 2022073911 W CN2022073911 W CN 2022073911W WO 2022161377 A1 WO2022161377 A1 WO 2022161377A1
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- A61K9/2022—Organic macromolecular compounds
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Definitions
- the invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition of a glucopyranosyl derivative as an inhibitor of sodium-dependent glucose transporters (SGLTs) and a preparation method thereof.
- SGLTs sodium-dependent glucose transporters
- SGLTs Sodium-dependent glucose transporters
- SLC solute carriers
- SGLTs inhibitors will not decrease with the severe insulin resistance or ⁇ -cell failure.
- SGLTs inhibitors could be used alone or in combination with other hypoglycemic agents. Therefore, SGLTs inhibitors are ideal and novel hypoglycemic agents.
- SGLTs inhibitors can be used for treating diabetes-related complications. Such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolic disorder, hyperinsulinemia, hyperlipidemia, obesity, and so on. Meanwhile, SGLTs inhibitors can also be used in combination with current treatment regimens, such as sulphonamides, thiazolidinedione, metformin, and insulin, etc., which can reduce the dose without impacting on the effectiveness of the medicine, thereby avoiding or reducing side effects, and improving patient compliance.
- current treatment regimens such as sulphonamides, thiazolidinedione, metformin, and insulin, etc.
- WO 2016173425 discloses a sodium-dependent glucose transporters (SGLTs) inhibitor, the structure of which is shown in formula (I) ,
- WO 2017088839 discloses a complex comprising the compound having formula (I) , L-pyroglutamic acid and water, and its structure is as shown in formula (II) ,
- the present invention provides a pharmaceutical composition comprising the compound having formula (I) , (I-A) , (II) or (II-A) .
- the pharmaceutical composition of the present invention can effectively improve the dissolution and fluidity of the drug, and has high content uniformity, stable quality and high bioavailability.
- the present invention relates to a pharmaceutical composition, comprising:
- the pharmaceutical composition of the present invention comprises:
- the specification of the pharmaceutical composition of the present invention is 5 mg-50 mg.
- the pharmaceutical composition of the present invention comprises:
- the solvates of the present invention include hydrates.
- the complex described in the present invention comprises a drug co-crystal, wherein the drug co-crystal means the specific crystal structure formed by the intermolecular force (hydrogen bond, halogen bond, ⁇ stacking effect and/or van der Waals force) between the compound having formula (I) and the pharmaceutically acceptable ligand through molecular recognition without breaking the chemical bond of the compound having formula (I) .
- the drug co-crystal means the specific crystal structure formed by the intermolecular force (hydrogen bond, halogen bond, ⁇ stacking effect and/or van der Waals force) between the compound having formula (I) and the pharmaceutically acceptable ligand through molecular recognition without breaking the chemical bond of the compound having formula (I) .
- the complex is a complex formed by the compound having formula (I) and L-pyroglutamic acid, wherein the molar ratio of the compound having formula (I) to L-pyroglutamic acid is 1: 1, and has the structure as shown in formula (I-A) ,
- the complex described in the present invention is a hydrate.
- the complex of the present invention has the structure as shown in formula (II-A) ,
- x is 1-1.5; preferably, x is 1-1.25; more preferably, x is 1.25.
- the complex of the present invention contains 1.25 water molecules, and has the structure as shown in formula (II) ,
- the filler of the present invention is corn starch, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, starch, glucose, fructose, xylitol, sorbitol, calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin, maltodextrin, maltitol or any combination thereof.
- the filler of the present invention is calcium hydrogen phosphate.
- the filler of the present invention is a combination of lactose and microcrystalline cellulose.
- the filler of the present invention is a combination of mannitol and microcrystalline cellulose.
- the filler of the present invention is a combination of mannitol and pregelatinized starch.
- the filler of the present invention is dextrin. In some embodiments, the filler of the present invention is maltodextrin.
- the filler of the present invention is a combination of lactose, microcrystalline cellulose and pregelatinized starch.
- the lactose described in the present invention is lactose monohydrate or anhydrous lactose.
- the filler of the present invention is corn starch.
- the pharmaceutical composition of the present invention optionally further comprises one or more disintegrants.
- the pharmaceutical composition of the present invention optionally further comprises one or more surfactants.
- the pharmaceutical composition of the present invention optionally further comprises one or more lubricants.
- the pharmaceutical composition of the present invention optionally further comprises one or more glidants.
- the pharmaceutical composition of the present invention further comprises:
- the disintegrant of the present invention is croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, starch, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate or any combination thereof.
- the surfactant of the present invention is sodium lauryl sulfate, Tween 80, hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, poloxamer or any combination of them.
- the lubricant of the present invention is stearic acid, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, polyethylene glycol, carnauba wax, sodium lauryl sulfate, glyceryl palmitate stearate, palmitic acid, myristic acid, hydrogenated vegetable oil, fat or any combination thereof.
- the glidant of the present invention is silicon dioxide, magnesium silicate, magnesium trisilicate, talc, micronized silica gel (also known as colloidal silicon dioxide) or any combination thereof.
- the pharmaceutical composition of the present invention optionally further comprises one or more binders.
- the binder of the present invention is hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, ethyl cellulose or any combination thereof.
- the pharmaceutical composition of the present invention optionally further comprises a coating agent, wherein the coating agent comprises a coating polymer.
- the coating agent of the present invention optionally further comprises one or more of the following substances: one or more plasticizers, one or more anti-adhesive agents, one or more glidants, one or more sunscreen agents and one or more colorants.
- the coating polymer of the present invention is hydroxypropyl methyl cellulose, polyvinyl alcohol, hydroxypropyl cellulose, ethyl cellulose, methacrylic acid polymer, ethylene-vinyl acetate copolymer or any combination thereof.
- the plasticizer is selected from glycerol triacetate, diethyl phthalate, tributyl sebacate, polyethylene glycol, glycerin, triethyl citrate or any combination thereof. In some embodiments, the plasticizer is selected from polyethylene glycol with a molecular weight of 200-20,000. In some embodiments, the plasticizer is selected from polyethylene glycol with a molecular weight of 400-6,000.
- the anti-adhesive agent of the present invention is selected from talc, glyceryl monostearate, micronized silica gel, and any combination thereof.
- the sunscreen agent of the present invention is titanium dioxide.
- the compound having formula (I) in the pharmaceutical composition of the present invention, accounts for less than 25%of the weight of the pharmaceutical composition. In some embodiments, in the pharmaceutical composition of the present invention, the compound having formula (I) , calculated as a percentage by weight, accounts for 2.5%-20%of the weight of the pharmaceutical composition. In some embodiments, in the pharmaceutical composition of the present invention, the compound having formula (I) , calculated as a percentage by weight, accounts for 5.0%-15%, 5.0%-14%, 7.0%-14.0%, 7.1%-13.5%, 7.0%-11.0%, or 7.1%-10.5%of the weight of the pharmaceutical composition.
- the dissolution of the pharmaceutical composition is good.
- the active ingredient of the pharmaceutical composition is a salt or complex of the compound having formula (I)
- the amount of the active ingredient can be converted according to the molecular mass ratio.
- the filler of the present invention calculated as a percentage by weight, accounts for 2%-95%of the weight of the pharmaceutical composition.
- the filler of the present invention calculated as a percentage by weight, accounts for 10%-90%of the weight of the pharmaceutical composition.
- the filler of the present invention calculated as a percentage by weight, accounts for 54%-90%, 55%-90%, 54%-87%, 55%-87%, 54%-82%or 55%-82%of the weight of the pharmaceutical composition.
- the filler of the present invention calculated as a percentage by weight, accounts for 70%-90%, 74%-87%or 75%-86%of the weight of the pharmaceutical composition.
- fillers are compensatory fillers. Its weight can vary according to the actual amount of the compound having formula (I) or the pharmaceutically acceptable salt, solvate or complex thereof, and/or other pharmaceutically acceptable adjuvants used (such as disintegrants, surfactants, lubricants, wetting agents, binders, coating agents or any combination thereof) .
- the disintegrant of the present invention calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
- the disintegrant of the present invention calculated as a percentage by weight, accounts for 0-15%of the weight of the pharmaceutical composition.
- the disintegrant of the present invention calculated as a percentage by weight, accounts for 0.5%-15%, 1%-15%, 1.5%-15%, 2%-15%, 2%-4%or 3%of the weight of the pharmaceutical composition.
- the disintegrant of the present invention calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%or 20%of the weight of the pharmaceutical composition.
- the surfactant of the present invention calculated as a percentage by weight, accounts for 0-15%or more of the weight of the pharmaceutical composition.
- the surfactant of the present invention calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
- the surfactant of the present invention calculated as a percentage by weight, accounts for 0-8%of the weight of the pharmaceutical composition.
- the surfactant of the present invention calculated as a percentage by weight, accounts for 0.5%-15%, 0.5%-10%, 0.5%-8%, 0.5%-5%, 0.5%-3%, 0-3%, 0.5%-2%, 0.5%-1.5%, 0.5%-1%or 1%-3%of the weight of the pharmaceutical composition.
- the surfactant of the present invention calculated as a percentage by weight, accounts for 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%or 15%of the weight of the pharmaceutical composition.
- the lubricant of the present invention calculated as a percentage by weight, accounts for 0-8%of the weight of the pharmaceutical composition.
- the lubricant of the present invention calculated as a percentage by weight, accounts for 0-5%of the weight of the pharmaceutical composition.
- the lubricant of the present invention calculated as a percentage by weight, accounts for 0.5%-8%, 0.5%-5%, 0.5%-3%, or 1.5%-2%of the weight of the pharmaceutical composition.
- the lubricant of the present invention calculated as a percentage by weight, accounts for 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%or 8%of the weight of the pharmaceutical composition.
- the glidant of the present invention calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
- the glidant of the present invention calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
- the glidant of the present invention calculated as a percentage by weight, accounts for 0.5%-20%, 0.5%-10%, 0.5%-2%, 0.5%-1%, 1%-20%, 1%-10%, 1%-2%or 1%of the weight of the pharmaceutical composition.
- the binder of the present invention calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
- the binder of the present invention calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
- the binder of the present invention calculated as a percentage by weight, accounts for 0-8%, 0-5%, 0-4%or 0-3%of the weight of the pharmaceutical composition.
- the binder of the present invention calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 10%, 15%or 20%of the weight of the pharmaceutical composition.
- the coating agent of the present invention calculated as a percentage by weight, accounts for 0-5%of the weight of the pharmaceutical composition.
- the coating polymer of the present invention calculated as a percentage by weight, accounts for 10%-95%of the weight of the coating agent.
- the coating polymer of the present invention calculated as a percentage by weight, accounts for 20%-90%of the weight of the coating agent.
- the coating polymer of the present invention calculated as a percentage by weight, accounts for 30%-60%of the weight of the coating agent.
- the plasticizer of the present invention calculated as a percentage by weight, accounts for 0-35%of the weight of the coating agent.
- the plasticizer of the present invention calculated as a percentage by weight, accounts for 15%-30%of the weight of the coating agent.
- the anti-adhesive agent of the present invention calculated as a percentage by weight, accounts for 0-30%of the weight of the coating agent. In some embodiments, the anti-adhesive agent of the present invention, calculated as a percentage by weight, accounts for 10%-25%of the weight of the coating agent.
- the colorant of the present invention calculated as a percentage by weight, accounts for 0-20%of the weight of the coating agent. In some embodiments, the colorant of the present invention, calculated as a percentage by weight, accounts for 5%-15%of the weight of the coating agent.
- the pharmaceutical preparation of the present invention can be packaged in any package that promotes the stability of the pharmaceutical preparation.
- bottled, aluminum-plastic packaging materials, or double-aluminum packaging materials can be used.
- the pharmaceutical composition of the present invention comprises:
- filler is a combination of lactose and microcrystalline cellulose; or the filler is a combination of mannitol and microcrystalline cellulose; or the filler is a combination of mannitol and pregelatinized starch; or the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch;
- disintegrant includes but is not limited to croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof;
- surfactant includes but is not limited to sodium lauryl sulfate;
- lubricant optionally, one or more lubricants, wherein the lubricant includes but is not limited to magnesium stearate; and/or
- glidant includes but is not limited to micronized silica gel.
- the pharmaceutical composition of the present invention comprises:
- filler is a combination of lactose and microcrystalline cellulose; or the filler is a combination of mannitol and microcrystalline cellulose; or the filler is a combination of mannitol and pregelatinized starch; or the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch;
- disintegrant includes but is not limited to croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof;
- surfactant includes but is not limited to sodium lauryl sulfate;
- glidant optionally, one or more glidants, wherein the glidant includes but is not limited to micronized silica gel; and/or
- binder optionally, one or more binders, wherein the binder includes but is not limited to hydroxypropyl methylcellulose.
- the pharmaceutical composition of the present invention comprises:
- filler (s) calculated as a percentage by weight, account (s) for 10%-90%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition
- disintegrant (s) calculated as a percentage by weight, account (s) for 0-15%of the weight of the pharmaceutical composition
- surfactant (s) calculated as a percentage by weight, account (s) for 0-15%, 0-8%, 0.5%-15%or 0.5%-8%of the weight of the pharmaceutical composition;
- glidant (s) calculated as a percentage by weight, account (s) for 0-10%of the weight of the pharmaceutical composition.
- the pharmaceutical composition of the present invention comprises:
- filler (s) calculated as a percentage by weight, account (s) for 10%-90%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition
- disintegrant (s) calculated as a percentage by weight, account (s) for 0-15%of the weight of the pharmaceutical composition
- surfactant (s) calculated as a percentage by weight, account (s) for 0-15%or 0-8%of the weight of the pharmaceutical composition
- glidant (s) calculated as a percentage by weight, account (s) for 0-10%of the weight of the pharmaceutical composition
- binder (s) calculated as a percentage by weight, account (s) for 0-20%or 0-10%of the weight of the pharmaceutical composition
- the combination of lactose and microcrystalline cellulose of the present invention accounts for 10%-90%, 15%-87%, 15%-85%, 75%-86%or 78%-87%of the weight of the pharmaceutical composition.
- the weight ratio of lactose to microcrystalline cellulose of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 2: 3, 2: 1, 1: 1, 2.5: 1, 3.5: 1, 4: 1 or 5: 1.
- the combination of mannitol and microcrystalline cellulose of the present invention accounts for 10%-90%, 54%-87%, or 74%-77%of the weight of the pharmaceutical composition.
- the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 1, 1: 2, 2: 3, 1: 3, 1: 4, 2: 1, 2: 5, 3: 1, 4: 1 or 5: 1.
- the combination of mannitol and pregelatinized starch of the present invention accounts for 10%-90%or 79%-87%of the weight of the pharmaceutical composition.
- the weight ratio of mannitol to pregelatinized starch of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of mannitol to pregelatinized starch of the present invention is 2: 3.
- the combination of lactose, microcrystalline cellulose and pregelatinized starch accounts for 15%-90%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition.
- the combination of lactose, microcrystalline cellulose and pregelatinized starch accounts for 75%-85%or 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition.
- the disintegrant (s) of the present invention e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- the sodium lauryl sulfate of the present invention calculated as a percentage by weight, accounts for 0-15%, 0-8%, 0.5%-15%or 0.5%-8%of the weight of the pharmaceutical composition.
- the magnesium stearate of the present invention accounts for 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition.
- the micronized silica gel of the present invention calculated as a percentage by weight, accounts for 0.5%-10%or 0.5%-8%of the total weight of the pharmaceutical composition.
- the hydroxypropyl methylcellulose of the present invention calculated as a percentage by weight, accounts for 0-20%, 0-3%or 0.5%-5%of the total weight of the pharmaceutical composition.
- the combination of lactose and microcrystalline cellulose of the present invention accounts for 15%-87%, 15%-85%, 75%-86%or 79%-80%of the weight of the pharmaceutical composition.
- the weight ratio of lactose to microcrystalline cellulose of the present invention is 1: 3-5: 1. In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 2: 1, 1: 1, 2.5: 1, 3.5: 1, 4: 1, or 5: 1.
- the combination of mannitol and microcrystalline cellulose of the present invention accounts for 15%-87%, 15%-85%or 54%-87%of the weight of the pharmaceutical composition.
- the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 3-5: 1. In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 1, 1: 1.5, 1: 2, 2: 1, or 3: 1.
- the combination of mannitol and pregelatinized starch of the present invention accounts for 15%-87%, 15%-85%or 79%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of mannitol to pregelatinized starch is 1: 1.5 (i.e., 2: 3) .
- the combination of lactose, microcrystalline cellulose and pregelatinized starch of the present invention calculated as a percentage by weight, accounts for 15%-85%of the weight of the pharmaceutical composition; wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1.
- the combination of lactose, microcrystalline cellulose and pregelatinized starch of the present invention calculated as a percentage by weight, accounts for 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 9.5%-10.5%of the weight of the pharmaceutical composition; wherein the weight ratio of lactose to microcrystalline cellulose is 4: 1.
- the disintegrant (s) of the present invention e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- the disintegrant (s) of the present invention e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- account (s) for 2%-15%or 2%-4%of the weight of the pharmaceutical composition e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- the disintegrant (s) of the present invention e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- account (s) for 2%, 3%, 4%, 5%, 10%or 15%of the weight of the pharmaceutical composition e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof
- the sodium lauryl sulfate of the present invention accounts for 0-15%, 0-8%, 0.5%-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition. In some embodiments, the sodium lauryl sulfate of the present invention, calculated as a percentage by weight, accounts for 0.5%, 0.75%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 8%, 10%or 15%of the weight of the pharmaceutical composition.
- the magnesium stearate of the present invention calculated as a percentage by weight, accounts for 0.5%-8%, 0.5%-5%or 0.5%-2%of the weight of the pharmaceutical composition. In some embodiments, the magnesium stearate of the present invention, calculated as a percentage by weight, accounts for 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 5%, 6%, 7%or 8%of the weight of the pharmaceutical composition.
- the micronized silica gel of the present invention calculated as a percentage by weight, accounts for 0.5%-10%, 0.5%-5%or 0.5%-2%of the total weight of the pharmaceutical composition. In some embodiments, the micronized silica gel of the present invention, calculated as a percentage by weight, accounts for 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%or 10%of the total weight of the pharmaceutical composition.
- the hydroxypropyl methylcellulose of the present invention calculated as a percentage by weight, accounts for 0-20%, 0-10%or 1%-5%of the total weight of the pharmaceutical composition. In some embodiments, the hydroxypropyl methylcellulose of the present invention, calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 10%, 15%or 20%of the total weight of the pharmaceutical composition.
- the pharmaceutical composition of the present invention comprises:
- filler (s) calculated as a percentage by weight, account (s) for 15%-85%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition;
- the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1; or
- the filler is a combination of mannitol and microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1; or
- the filler is a combination of mannitol and pregelatinized starch, and the weight ratio of mannitol to pregelatinized starch is 1: 1.5; or
- the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%, 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%, 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%, 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1;
- disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof, and the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition;
- surfactant includes but is not limited to sodium lauryl sulfate; optionally, the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition;
- lubricant includes but is not limited to magnesium stearate; optionally, the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-3%or 0.5%-2%of the weight of the pharmaceutical composition; and
- glidant includes but is not limited to micronized silica gel; optionally, the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition.
- the pharmaceutical composition of the present invention comprises:
- filler (s) calculated as a percentage by weight, account (s) for 15%-85%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition;
- the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1; or
- the filler is a combination of mannitol and microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1; or
- the filler is a combination of mannitol and pregelatinized starch, and the weight ratio of mannitol to pregelatinized starch is 1: 1.5; or
- the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1;
- disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof, and the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition;
- surfactant includes but is not limited to sodium lauryl sulfate; optionally, the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition;
- lubricant includes but is not limited to magnesium stearate; optionally, the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-3%or 0.5%-2%of the weight of the pharmaceutical composition;
- glidant includes but is not limited to micronized silica gel; optionally, the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition;
- binder optionally, one or more binders, wherein the binder includes but is not limited to hydroxypropyl methylcellulose; optionally, the hydroxypropyl methylcellulose, calculated as a percentage by weight, accounts for 1%-5%of the total weight of the pharmaceutical composition.
- the combination of lactose, microcrystalline cellulose and pregelatinized starch accounts for 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 9.5%-10.5%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 4: 1.
- the pharmaceutical composition of the present invention is a solid pharmaceutical preparation.
- the solid pharmaceutical preparation is a powder, granule, tablet, capsule or pill.
- the pharmaceutical composition of the present invention is administered once, twice, three times or four times a day.
- the pharmaceutical composition of the present invention further comprises other additional therapeutic agents, wherein the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an anti-hyperglycemic agent, an anti-obesity drug, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or any combination thereof.
- the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an anti-hyperglycemic agent, an anti-obesity drug, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or any combination thereof.
- the anti-diabetic agent other than an SGLT-2 inhibitor or anti-hyperglycemic agent is independently a biguanide drug, a sulfonylurea drug, a glucosidase inhibitor, a PPAR agonist (peroxisome proliferator activated receptor agonist) , an ⁇ P2 inhibitor (adipocyte fatty acid binding protein inhibitor) , a PPAR ⁇ / ⁇ dual agonist (peroxisome proliferator activated receptor ⁇ / ⁇ dual activator) , a dipeptidyl peptidase IV (DPP-IV) inhibitor, a glinide drug, insulin, a glucagon-like peptide-1 (GLP-1) inhibitor, a PTP1B inhibitor (protein tyrosine phosphatase 1B inhibitor) , a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor or any combination thereof.
- a biguanide drug a sulfonylurea
- the lipid-lowering agent is an MTP inhibitor (microsomal triglyceride transfer protein inhibitor) , an HMGCoA reductase inhibitor (hydroxymethylglutaryl coenzyme A reductase inhibitor) , a squalene synthase inhibitor, a butyric acid-based lipid-lowering drug, an ACAT inhibitor (acetylcholesterol acetyltransferase inhibitor) , a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na (+) /bile acid cotransporter inhibitor, an upregulator of LDL receptor activity (up-regulator of low-density lipoprotein receptor activity) , niacin-like lipid-lowering drugs (such as niacin or a derivative thereof) , a bile acid sequestrant or any combination thereof.
- MTP inhibitor microsomal triglyceride transfer protein inhibitor
- HMGCoA reductase inhibitor hydroxymethylglutaryl coen
- the lipid-lowering agent is pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, rosuvastatin or any combination thereof.
- provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting SGLT-2.
- provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting SGLT-1.
- provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for increasing the level of high-density lipoprotein.
- provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- diabetes diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- composition disclosed herein for use in inhibiting SGLT-2.
- composition disclosed herein for use in inhibiting SGLT-1.
- composition disclosed herein for use in increasing the level of high-density lipoprotein.
- the pharmaceutical composition disclosed herein for use in preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- diabetes diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- provided herein is a method of inhibiting SGLT-2 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
- provided herein is a method of inhibiting SGLT-1 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
- provided herein is a method of increasing the level of high-density lipoprotein in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
- a method of preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases in a subject comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- diabetes diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
- the present invention also provides a method for preparing the pharmaceutical composition, which is simple and easy to implement, has good stability and high safety, and is suitable for industrial production.
- the present invention provides a method for preparing the pharmaceutical composition of the present invention, comprising the following steps: a compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and one or more pharmaceutically acceptable adjuvants of the present invention are mixed together in any desired order to form a total mixed powder, and the required amount of the total mixed powder is filled into capsules or formed into tablets.
- the method for forming tablets according to the present invention includes but is not limited to the method of wet granulation, dry granulation or direct powder compression.
- the present invention relates to a method for preparing the pharmaceutical composition, comprising the following steps:
- the lubricants and the premix are mixed uniformly to obtain a total mixed powder
- the present invention relates to a preparation method of the pharmaceutical composition, comprising the following steps:
- the lubricants and the premix are mixed uniformly to obtain a total mixed powder
- the present invention relates to a preparation method of the pharmaceutical composition, comprising the following steps:
- the preparation method of the pharmaceutical composition of the present invention further comprises the following step: coating plain tablets to obtain coated tablets.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound having formula (I) , (II) , (I-A) and/or (II-A) or a pharmaceutically acceptable salt, a solvate or a complex thereof, and a method for preparing the pharmaceutical composition, and also relates to the pharmaceutical application of the pharmaceutical composition.
- pharmaceutically acceptable refers to that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
- pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
- pharmaceutically acceptable salt refers to organic or inorganic salts of a compound disclosed herein.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.
- solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
- solvent molecules include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid, ethanolamine, etc.
- DMSO dimethylsulfoxide
- hydrate refers to the complex where the solvent molecule is water.
- pharmaceutically acceptable adjuvant refers to the excipients and additives used in the production of medicines and formulating prescriptions. In addition to the active ingredients, they have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations.
- Common pharmaceutically acceptable adjuvants include, but are not limited to, filler, wetting agent, lubricant, glidant, surfactant, binder, disintegrant, coating agent, flavoring agent, film-forming agent, antioxidant, protective agent, solvent, propellant, solubilizer, cosolvent, emulsifier, coloring agent, osmotic pressure regulator, stabilizer, plasticizer, anti-adhesive, anti-caking agent, pressure aid, bacteriostatic agent, pH regulator, etc.
- treatment is meant to include preventing, alleviating, stopping or reversing the progress and severity of the condition and symptoms being treated. Therefore, the present invention includes medical treatment and/or prophylactic administration.
- the term “effective amount” refers to the amount of a pharmaceutical preparation that is effective for the treatment of conditions and symptoms.
- the “subject” in the present invention refers to an animal who can benefit from the pharmaceutical composition and/or treatment method of the present invention, preferably a mammal, more preferably a primate including lower primates and more preferably a human.
- a subject, whether it is a human or non-human animal, can be referred to as an individual, patient, animal, host, or recipient.
- equivalent amount refers to an equivalent molar amount
- an equivalent amount of compound having formula (II-A) ” in “the complex having formula (II) or an equivalent amount of compound having formula (II-A) is weighed” means that the molar amount of the compound having the formula (II-A) is the same as the molar amount of the compound having the formula (II) , that is, the mass of the drug molecule (i.e., the compound having the formula (I) ) in the two is the same.
- the numerical range from N 1 to N 2 , N 1 -N 2 or N 1 ⁇ N 2 means that the range includes the endpoints N 1 and N 2 and any numerical value in the interval, for example, the numerical range 1 ⁇ 5 means that the range includes 1, 5, and any number between 1 and 5.
- the active ingredient may be the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof.
- the active ingredient is a complex having formula (I-A) , (II-A) or (II) , it can be replaced by a compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof, and the corresponding amount can be converted after measuring the water content.
- the mass of the compound having formula (I) is theoretically 77.74%of the mass of the compound having formula (I-A) .
- the mass of the compound having formula (I) is theoretically 74.83%-75.40%of the mass of the compound having formula (II-A) . In some embodiments, when x is 1.25, the mass of the compound having formula (I) is theoretically 74.83%of the mass of the compound having formula (II-A) ; in some embodiments, when x is 1, the mass of the compound having formula (I) is theoretically 75.40%of the mass of the compound having formula (II-A) .
- Example 1 The formulation and preparation process of capsules containing different proportions of fillers
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 2 The formulation and preparation process of capsules containing different proportions of surfactants
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 3 The formulation and preparation process of capsules containing different proportions of disintegrants
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 4 The formulation and preparation process of capsules containing different proportions of glidants
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 5 The formulation and preparation process of capsules containing different proportions of lubricants
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 6 The formulation and preparation process of capsules containing different proportions of fillers
- the content of the compound having formula (I) in each capsule is 5 mg.
- Example 7 The formulation and preparation process of capsules containing different proportions of surfactants
- the content of the compound having formula (I) in each capsule is 5 mg.
- Example 8 The formulation and preparation process of capsules containing different proportions of disintegrants
- the content of the compound having formula (I) in each capsule is 5 mg.
- Example 9 The formulation and preparation process of capsules containing different proportions of glidants
- the content of the compound having formula (I) in each capsule is 5 mg.
- Example 10 The formulation and preparation process of capsules containing different proportions of lubricants
- the content of the compound having formula (I) in each capsule is 5 mg.
- Example 11 The formulation and preparation process of capsules containing different types of fillers
- the content of the compound having formula (I) in each capsule is 5 mg.
- capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
- Example 12 The formulation and preparation process of capsules containing different types of fillers
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 13 The formulation and preparation process of other capsules
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 14 The formulation and preparation process of other capsules
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 15 The formulation and preparation process of other capsules
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 16 The formulation and preparation process of other capsules
- the content of the compound having formula (I) in each capsule is 50 mg.
- Example 17 The formulation and preparation process of other capsules
- the content of the compound having formula (I) is 50 mg.
- Example 18 The formulation and preparation process of capsules with different particle sizes
- capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared by using active ingredients of different particle sizes, as shown in Samples 57-62.
- Formulation compound having formula (II-A) 66.84 mg, mannitol 111.26 mg, microcrystalline cellulose 166.90 mg, croscarmellose sodium 11.25 mg, sodium lauryl sulfate 3.75 mg, micronized silica gel 3.75 mg, magnesium stearate 11.25 mg.
- Example 19 The formulation and preparation process of tablets containing the compound having formula (I) or the complex having formula (II)
- the content of the compound having formula (I) in each tablet is 50 mg.
- Example 20 The formulation and preparation process of tablets containing different proportions of fillers
- the content of the compound having formula (I) in each tablet is 50 mg.
- Example 21 The formulation and preparation process of tablets containing different proportions of fillers
- the content of the compound having formula (I) in each tablet is 50 mg.
- Example 22 The formulation and preparation process of tablets containing different proportions of fillers
- the content of the compound having formula (I) in each tablet is 50 mg.
- Example 23 The formulation and preparation process of tablets containing different types of disintegrants
- the content of the compound having formula (I) in each tablet is 50 mg.
- Example 24 The formulation and preparation process of tablets containing different proportions of surfactants and/or lubricants
- the content of the compound having formula (I) in each tablet is 50 mg.
- Reagents sodium acetate trihydrate (analytical grade) , glacial acetic acid (analytical grade) , acetonitrile (chromatographic grade) , ultrapure water;
- Reference sample the complex having formula (II) .
- Dissolution method the capsule adopted the paddle method combined with the sedimentation basket, and the tablet adopted the paddle method
- Dissolution medium to a mixture of 2.99 g of sodium acetate trihydrate and 1.85 mL of glacial acetic acid was added purified water to a volume of 1000 mL. The mixture was stirred and dissolved completely, then glacial acetic acid was added to adjust the pH to 4.5. The resulting mixture was ready for use.
- Mobile phase A 350 mL of acetonitrile and 650 mL of ultrapure water were mixed thoroughly, and ultrasonically degassed for 10 min. The resulting mixture was ready for use.
- Diluent 500 mL of dissolution medium was filtered through a filter membrane, then 425 mL of filtrate and 75 mL of acetonitrile were added. The mixture was mixed thoroughly and ready for use.
- Blank solution 5 mL of dissolution medium was filtered through membrane, 2 mL of the initial filtrate was discarded, and the subsequent filtrate was taken and ready for use.
- Reference sample stock solution the complex having formula (II) (calculated by the compound having formula (I) , approximately 28 mg) was taken and accurately weighed, then placed in a 100 mL volumetric flask. 15 mL of acetonitrile was added to dissolve the solid completely, then about 65 mL of the dissolution medium filtered through the filter membrane was added. After 5 minutes of sonication, the mixture was diluted to the mark with the dissolution medium filtered through the filter membrane, and shaken thoroughly to obtain the reference sample stock solution. Two copies of the reference sample stock solution in parallel were prepared.
- Reference sample solution 2 mL each of the above reference sample stock solution was accurately measured, diluted with the diluent, and shaken thoroughly to prepare reference sample solutions containing about 0.0056 mg/mL, 0.0112 mg/mL, 0.0224 mg/mL, and 0.056 mg/mL of the compound having formula (I) respectively.
- Test sample solution 5 mL of the dissolution solution of the pharmaceutical composition of the present invention was taken at a specified time point, and quickly filtered with a filter membrane. 2 mL of the initial filtrate was discarded, and the subsequent filtrate was taken and ready for use.
- Chromatographic column Agilent ZORBAX Eclipse plus C18, 4.6 ⁇ 150mm, 5 ⁇ m (or other applicable chromatographic column) ;
- UV detector detection wavelength: 225 nm
- Injection volume 50 ⁇ L
- One injection of the test sample solution was taken and the chromatogram was recorded.
- the accompanying control was used during the injection process, that is, before the injection and after each injection of the test sample solution for about 4 hours, one injection of the reference sample solution was taken, and the samples were injected in sequence. At the end of the experiment, one injection of the reference sample solution was taken.
- the first 5 injections of the first reference sample solution and 1 injection of the accompanying control were used to calculate the RSD of the main peak area, which should not be greater than 2.0%; if there were multiple accompanying controls, the same method was used to calculate.
- the injection sequence is as shown in the table below.
- Reference sample solution 1 Name Number of injections Blank solution 1-2 Reference sample solution 6 Reference sample solution 2 Reference sample solution 1 Test sample solution 1 ... ... Reference sample solution 1 ... ... Reference sample solution 1
- test sample capsule or tablet
- formula (II) The dissolution of test sample (capsule or tablet) of the complex having formula (II) was calculated according to the following formula:
- a X The peak area of the test sample solution
- a S1 The average peak area of the reference sample solution (1 injection before and after the test sample solution) ;
- test results show that basically, the dissolution in vitro of the pharmaceutical composition of the present invention after 30 minutes is greater than 80% (acceptance standard: the dissolution after 30 minutes is not less than 80%) .
- the dissolution of the pharmaceutical compositions comprising active ingredients with different particle sizes was also determined in the present invention. From the dissolution data of Samples 57-62, it can be seen that the particle size of the active ingredient affects the dissolution of the pharmaceutical composition: when the particle size D90 of the active ingredient is about 61 ⁇ m, the dissolution of the pharmaceutical composition at 30 minutes is about 79%; and when the particle size D90 of the active ingredient is less than 61 ⁇ m, the dissolution of the pharmaceutical composition at 30 minutes is greater than 80%.
- Purpose to determine the content uniformity of the pharmaceutical composition of the present invention.
- HPLC high performance liquid chromatography
- Reagents ultrapure water, acetonitrile (chromatographically pure) ;
- Reference sample the complex having formula (II) .
- Blank solution/diluent 600 mL of acetonitrile and 400 mL of ultrapure water were mixed and shaken thoroughly for use.
- Mobile phase A 350 mL of acetonitrile and 650 mL of ultrapure water were mixed thoroughly, and ultrasonically degassed for 10 min. The resulting mixture was ready for use.
- Reference sample solution the complex having formula (II) (calculated by the compound having formula (I) , approximately 20 mg) was taken and accurately weighed, then placed in a 100 mL volumetric flask. 80 mL of the diluent was added, and the mixture was sonicated for 10 min to completely dissolve the solid. Then the mixture was diluted to the mark with the diluent, and shaken thoroughly to prepare a reference sample solution containing about 0.2 mg/mL of the compound having formula (I) . Two copies of the reference sample solution in parallel were prepared.
- Test sample solution one capsule prepared by the present invention was taken, the capsule shell was open, and the contents were poured out. The contents together with the capsule shell were placed in a volumetric flask, or one tablet prepared by the present invention was placed it in a volumetric flask, then diluted with diluent, shaken thoroughly to prepare a test sample solution containing about 0.2 mg/mL of the compound having formula (I) ; 10 copies of the test sample solution in parallel were prepared.
- Chromatographic column Agilent ZORBAX Eclipse plus C18, 4.6 ⁇ 150 mm, 5 ⁇ m (or other suitable chromatographic column) ;
- UV detector detection wavelength: 225 nm
- Injection volume 10 ⁇ L
- composition containing the complex having formula (II) was calculated according to the following formula:
- a S1 The average peak area of the reference sample solution (1 injection before and after the test sample solution) ;
- a x The peak area of the test sample solution
- test sample capsule or tablet
- complex having formula (II) , based on C 23 H 27 ClO 7 , mg
- Mean value that is, the average relative content of each capsule/tablet with a labeled amount of 100
- n The number of test sample
- A The absolute value of the difference between the labeled amount and the mean value
- test results show that the content uniformity of the pharmaceutical compositions of the present invention meets the regulations of the 2015 edition of the Chinese Pharmacopoeia.
Abstract
Provided are a pharmaceutical composition comprising a glucopyranosyl derivative and a preparation method thereof. The pharmaceutical composition can effectively improve the dissolution and fluidity of the drug, and has high content uniformity, stable quality and high bioavailability.
Description
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the priority and benefit of Chinese Patent Application No. 202110109107. X, filed with the State Intellectual Property Office of China on January 27, 2021, which is incorporated herein by reference in its entirety.
The invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition of a glucopyranosyl derivative as an inhibitor of sodium-dependent glucose transporters (SGLTs) and a preparation method thereof.
Sodium-dependent glucose transporters (SGLTs) are a superfamily of solute carriers (SLC) , among which SGLT-1 and SGLT-2 are the two most studied family members. In biological bodies, glucose is transported by SGLTs through active transport against a concentration gradient with simultaneous energy consumption. Research indicates that normally plasma glucose is filtered in the kidney glomeruli in which 90%of glucose in the early S1 segment of the renal tubule is actively transported to epithelial cells by SGLT-2 and 10%of glucose in the distal S3 segment of the renal tubule is actively transported to epithelial cells by SGLT-1, and then transported to peripheral capillary network by glucose transporters (GLUTs) on the basement membrane side of epithelial cells, completing the reabsorption of glucose by the renal tubules. Hence, SGLTs is the first stage in regulation of glucose metabolism in cells, and an ideal target for treating diabetes effectively. It has been found by research that the patients with SGLT-2 impairment would excrete large amounts of urine glucose. This provides the factual basis of treating diabetes by reducing glucose uptake through inhibiting SGLT-2 activity. Therefore, inhibiting activity of SGLTs transport protein could block reabsorption of glucose in renal tubules and increase excretion of glucose in urine to normalize the plasma glucose concentration and further control the diabetes and diabetic complications. Inhibiting SGLTs would not influence the normal anti-regulatory mechanism of glucose, which may cause the risk of hypoglycemia. Meanwhile, lowering blood glucose through an increase of renal glucose excretion could promote weight loss in obese patients. It has also been found by research that the mechanism of action of SGLTs inhibitors is independent of pancreatic β cell dysfunction or the degree of insulin resistance. Therefore, the efficacy of SGLTs inhibitors will not decrease with the severe insulin resistance or β-cell failure. SGLTs inhibitors could be used alone or in combination with other hypoglycemic agents. Therefore, SGLTs inhibitors are ideal and novel hypoglycemic agents.
In addition, it has also been found by research that SGLTs inhibitors can be used for treating diabetes-related complications. Such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolic disorder, hyperinsulinemia, hyperlipidemia, obesity, and so on. Meanwhile, SGLTs inhibitors can also be used in combination with current treatment regimens, such as sulphonamides, thiazolidinedione, metformin, and insulin, etc., which can reduce the dose without impacting on the effectiveness of the medicine, thereby avoiding or reducing side effects, and improving patient compliance.
WO 2016173425 discloses a sodium-dependent glucose transporters (SGLTs) inhibitor, the structure of which is shown in formula (I) ,
WO 2017088839 discloses a complex comprising the compound having formula (I) , L-pyroglutamic acid and water, and its structure is as shown in formula (II) ,
Currently, there is no research on a pharmaceutical composition comprising the compound having formula (I) or the compound having formula (II) in the prior art.
SUMMARY OF THE INVENTION
The inventors found through research that the compound having formula (I) , (I-A) , (II) or (II-A) has poor fluidity and a slow dissolution, which is not conducive to the absorption of the drug. Based on the shortcomings of the active pharmaceutical ingredient itself, the present invention provides a pharmaceutical composition comprising the compound having formula (I) , (I-A) , (II) or (II-A) . The pharmaceutical composition of the present invention can effectively improve the dissolution and fluidity of the drug, and has high content uniformity, stable quality and high bioavailability.
More specifically:
The present invention relates to a pharmaceutical composition, comprising:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
and pharmaceutically acceptable adjuvants.
In some embodiments, the specification of the pharmaceutical composition of the present invention is 5 mg-50 mg.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers.
The solvates of the present invention include hydrates.
The complex described in the present invention comprises a drug co-crystal, wherein the drug co-crystal means the specific crystal structure formed by the intermolecular force (hydrogen bond, halogen bond, π stacking effect and/or van der Waals force) between the compound having formula (I) and the pharmaceutically acceptable ligand through molecular recognition without breaking the chemical bond of the compound having formula (I) .
In some embodiments, the complex is a complex formed by the compound having formula (I) and L-pyroglutamic acid, wherein the molar ratio of the compound having formula (I) to L-pyroglutamic acid is 1: 1, and has the structure as shown in formula (I-A) ,
In some embodiments, the complex described in the present invention is a hydrate.
In some embodiments, the complex of the present invention has the structure as shown in formula (II-A) ,
wherein, x is 1-1.5; preferably, x is 1-1.25; more preferably, x is 1.25.
In some embodiments, the complex of the present invention contains 1.25 water molecules, and has the structure as shown in formula (II) ,
In some embodiments, the filler of the present invention is corn starch, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, starch, glucose, fructose, xylitol, sorbitol, calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin, maltodextrin, maltitol or any combination thereof.
In some embodiments, the filler of the present invention is calcium hydrogen phosphate.
In some embodiments, the filler of the present invention is a combination of lactose and microcrystalline cellulose.
In some embodiments, the filler of the present invention is a combination of mannitol and microcrystalline cellulose.
In some embodiments, the filler of the present invention is a combination of mannitol and pregelatinized starch.
In some embodiments, the filler of the present invention is dextrin. In some embodiments, the filler of the present invention is maltodextrin.
In some embodiments, the filler of the present invention is a combination of lactose, microcrystalline cellulose and pregelatinized starch.
In some embodiments, the lactose described in the present invention is lactose monohydrate or anhydrous lactose.
In some embodiments, the filler of the present invention is corn starch.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises one or more disintegrants.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises one or more surfactants.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises one or more lubricants.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises one or more glidants.
In some embodiments, the pharmaceutical composition of the present invention further comprises:
c) optionally one or more disintegrants;
d) optionally one or more surfactants;
e) optionally one or more lubricants; and/or
f) optionally one or more glidants.
In some embodiments, the disintegrant of the present invention is croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, starch, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate or any combination thereof.
In some embodiments, the surfactant of the present invention is sodium lauryl sulfate, Tween 80, hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, poloxamer or any combination of them.
In some embodiments, the lubricant of the present invention is stearic acid, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, polyethylene glycol, carnauba wax, sodium lauryl sulfate, glyceryl palmitate stearate, palmitic acid, myristic acid, hydrogenated vegetable oil, fat or any combination thereof.
In some embodiments, the glidant of the present invention is silicon dioxide, magnesium silicate, magnesium trisilicate, talc, micronized silica gel (also known as colloidal silicon dioxide) or any combination thereof.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises one or more binders.
In some embodiments, the binder of the present invention is hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, ethyl cellulose or any combination thereof.
In some embodiments, the pharmaceutical composition of the present invention optionally further comprises a coating agent, wherein the coating agent comprises a coating polymer.
In still other embodiments, the coating agent of the present invention optionally further comprises one or more of the following substances: one or more plasticizers, one or more anti-adhesive agents, one or more glidants, one or more sunscreen agents and one or more colorants.
In some embodiments, the coating polymer of the present invention is hydroxypropyl methyl cellulose, polyvinyl alcohol, hydroxypropyl cellulose, ethyl cellulose, methacrylic acid polymer, ethylene-vinyl acetate copolymer or any combination thereof.
In some embodiments, the plasticizer is selected from glycerol triacetate, diethyl phthalate, tributyl sebacate, polyethylene glycol, glycerin, triethyl citrate or any combination thereof. In some embodiments, the plasticizer is selected from polyethylene glycol with a molecular weight of 200-20,000. In some embodiments, the plasticizer is selected from polyethylene glycol with a molecular weight of 400-6,000.
In some embodiments, the anti-adhesive agent of the present invention is selected from talc, glyceryl monostearate, micronized silica gel, and any combination thereof.
In some embodiments, the sunscreen agent of the present invention is titanium dioxide.
In some embodiments, in the pharmaceutical composition of the present invention, the compound having formula (I) , calculated as a percentage by weight, accounts for less than 25%of the weight of the pharmaceutical composition. In some embodiments, in the pharmaceutical composition of the present invention, the compound having formula (I) , calculated as a percentage by weight, accounts for 2.5%-20%of the weight of the pharmaceutical composition. In some embodiments, in the pharmaceutical composition of the present invention, the compound having formula (I) , calculated as a percentage by weight, accounts for 5.0%-15%, 5.0%-14%, 7.0%-14.0%, 7.1%-13.5%, 7.0%-11.0%, or 7.1%-10.5%of the weight of the pharmaceutical composition. As decribed in the present invention, when the content of the compound having formula (I) in the pharmaceutical composition is within the defined range, the dissolution of the pharmaceutical composition is good. When the active ingredient of the pharmaceutical composition is a salt or complex of the compound having formula (I) , the amount of the active ingredient can be converted according to the molecular mass ratio.
In some embodiments, the filler of the present invention, calculated as a percentage by weight, accounts for 2%-95%of the weight of the pharmaceutical composition.
In some embodiments, the filler of the present invention, calculated as a percentage by weight, accounts for 10%-90%of the weight of the pharmaceutical composition.
In some embodiments, the filler of the present invention, calculated as a percentage by weight, accounts for 54%-90%, 55%-90%, 54%-87%, 55%-87%, 54%-82%or 55%-82%of the weight of the pharmaceutical composition.
In some embodiments, the filler of the present invention, calculated as a percentage by weight, accounts for 70%-90%, 74%-87%or 75%-86%of the weight of the pharmaceutical composition.
Those skilled in the art should recognize that fillers are compensatory fillers. Its weight can vary according to the actual amount of the compound having formula (I) or the pharmaceutically acceptable salt, solvate or complex thereof, and/or other pharmaceutically acceptable adjuvants used (such as disintegrants, surfactants, lubricants, wetting agents, binders, coating agents or any combination thereof) .
In some embodiments, the disintegrant of the present invention, calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
In some embodiments, the disintegrant of the present invention, calculated as a percentage by weight, accounts for 0-15%of the weight of the pharmaceutical composition.
In some embodiments, the disintegrant of the present invention, calculated as a percentage by weight, accounts for 0.5%-15%, 1%-15%, 1.5%-15%, 2%-15%, 2%-4%or 3%of the weight of the pharmaceutical composition.
In some embodiments, the disintegrant of the present invention, calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%or 20%of the weight of the pharmaceutical composition.
In some embodiments, the surfactant of the present invention, calculated as a percentage by weight, accounts for 0-15%or more of the weight of the pharmaceutical composition.
In some embodiments, the surfactant of the present invention, calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
In some embodiments, the surfactant of the present invention, calculated as a percentage by weight, accounts for 0-8%of the weight of the pharmaceutical composition.
In some embodiments, the surfactant of the present invention, calculated as a percentage by weight, accounts for 0.5%-15%, 0.5%-10%, 0.5%-8%, 0.5%-5%, 0.5%-3%, 0-3%, 0.5%-2%, 0.5%-1.5%, 0.5%-1%or 1%-3%of the weight of the pharmaceutical composition.
In some embodiments, the surfactant of the present invention, calculated as a percentage by weight, accounts for 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%or 15%of the weight of the pharmaceutical composition.
In some embodiments, the lubricant of the present invention, calculated as a percentage by weight, accounts for 0-8%of the weight of the pharmaceutical composition.
In some embodiments, the lubricant of the present invention, calculated as a percentage by weight, accounts for 0-5%of the weight of the pharmaceutical composition.
In some embodiments, the lubricant of the present invention, calculated as a percentage by weight, accounts for 0.5%-8%, 0.5%-5%, 0.5%-3%, or 1.5%-2%of the weight of the pharmaceutical composition.
In some embodiments, the lubricant of the present invention, calculated as a percentage by weight, accounts for 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%or 8%of the weight of the pharmaceutical composition.
In some embodiments, the glidant of the present invention, calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
In some embodiments, the glidant of the present invention, calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
In some embodiments, the glidant of the present invention, calculated as a percentage by weight, accounts for 0.5%-20%, 0.5%-10%, 0.5%-2%, 0.5%-1%, 1%-20%, 1%-10%, 1%-2%or 1%of the weight of the pharmaceutical composition.
In some embodiments, the binder of the present invention, calculated as a percentage by weight, accounts for 0-20%of the weight of the pharmaceutical composition.
In some embodiments, the binder of the present invention, calculated as a percentage by weight, accounts for 0-10%of the weight of the pharmaceutical composition.
In some embodiments, the binder of the present invention, calculated as a percentage by weight, accounts for 0-8%, 0-5%, 0-4%or 0-3%of the weight of the pharmaceutical composition.
In some embodiments, the binder of the present invention, calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 10%, 15%or 20%of the weight of the pharmaceutical composition.
In some embodiments, the coating agent of the present invention, calculated as a percentage by weight, accounts for 0-5%of the weight of the pharmaceutical composition.
In some embodiments, the coating polymer of the present invention, calculated as a percentage by weight, accounts for 10%-95%of the weight of the coating agent.
In some embodiments, the coating polymer of the present invention, calculated as a percentage by weight, accounts for 20%-90%of the weight of the coating agent.
In some embodiments, the coating polymer of the present invention, calculated as a percentage by weight, accounts for 30%-60%of the weight of the coating agent.
In some embodiments, the plasticizer of the present invention, calculated as a percentage by weight, accounts for 0-35%of the weight of the coating agent.
In some embodiments, the plasticizer of the present invention, calculated as a percentage by weight, accounts for 15%-30%of the weight of the coating agent.
In some embodiments, the anti-adhesive agent of the present invention, calculated as a percentage by weight, accounts for 0-30%of the weight of the coating agent. In some embodiments, the anti-adhesive agent of the present invention, calculated as a percentage by weight, accounts for 10%-25%of the weight of the coating agent.
In some embodiments, the colorant of the present invention, calculated as a percentage by weight, accounts for 0-20%of the weight of the coating agent. In some embodiments, the colorant of the present invention, calculated as a percentage by weight, accounts for 5%-15%of the weight of the coating agent.
The pharmaceutical preparation of the present invention can be packaged in any package that promotes the stability of the pharmaceutical preparation. For example, bottled, aluminum-plastic packaging materials, or double-aluminum packaging materials can be used.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers; wherein the filler is a combination of lactose and microcrystalline cellulose; or the filler is a combination of mannitol and microcrystalline cellulose; or the filler is a combination of mannitol and pregelatinized starch; or the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch;
c) optionally, one or more disintegrants, wherein the disintegrant includes but is not limited to croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof;
d) optionally, one or more surfactants, wherein the surfactant includes but is not limited to sodium lauryl sulfate;
e) optionally, one or more lubricants, wherein the lubricant includes but is not limited to magnesium stearate; and/or
f) optionally, one or more glidants, wherein the glidant includes but is not limited to micronized silica gel.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers; wherein the filler is a combination of lactose and microcrystalline cellulose; or the filler is a combination of mannitol and microcrystalline cellulose; or the filler is a combination of mannitol and pregelatinized starch; or the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch;
c) optionally, one or more disintegrants, wherein the disintegrant includes but is not limited to croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof;
d) optionally, one or more surfactants, wherein the surfactant includes but is not limited to sodium lauryl sulfate;
e) optionally, one or more lubricants, wherein the lubricant includes but is not limited to magnesium stearate;
f) optionally, one or more glidants, wherein the glidant includes but is not limited to micronized silica gel; and/or
g) optionally, one or more binders, wherein the binder includes but is not limited to hydroxypropyl methylcellulose.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers, wherein the filler (s) , calculated as a percentage by weight, account (s) for 10%-90%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition;
c) optionally, one or more disintegrants, wherein the disintegrant (s) , calculated as a percentage by weight, account (s) for 0-15%of the weight of the pharmaceutical composition;
d) optionally, one or more surfactants, wherein the surfactant (s) , calculated as a percentage by weight, account (s) for 0-15%, 0-8%, 0.5%-15%or 0.5%-8%of the weight of the pharmaceutical composition;
e) optionally, one or more lubricants, wherein the lubricant (s) , calculated as a percentage by weight, account (s) for 0-8%or 0-5%of the weight of the pharmaceutical composition; and/or
f) optionally, one or more glidants, wherein the glidant (s) , calculated as a percentage by weight, account (s) for 0-10%of the weight of the pharmaceutical composition.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers, wherein the filler (s) , calculated as a percentage by weight, account (s) for 10%-90%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition;
c) optionally, one or more disintegrants, wherein the disintegrant (s) , calculated as a percentage by weight, account (s) for 0-15%of the weight of the pharmaceutical composition;
d) optionally, one or more surfactants, wherein the surfactant (s) , calculated as a percentage by weight, account (s) for 0-15%or 0-8%of the weight of the pharmaceutical composition;
e) optionally, one or more lubricants, wherein the lubricant (s) , calculated as a percentage by weight, account (s) for 0-8%or 0-5%of the weight of the pharmaceutical composition;
f) optionally, one or more glidants, wherein the glidant (s) , calculated as a percentage by weight, account (s) for 0-10%of the weight of the pharmaceutical composition; and/or
g) optionally, one or more binders, wherein the binder (s) , calculated as a percentage by weight, account (s) for 0-20%or 0-10%of the weight of the pharmaceutical composition;
In some embodiments, the combination of lactose and microcrystalline cellulose of the present invention, calculated as a percentage by weight, accounts for 10%-90%, 15%-87%, 15%-85%, 75%-86%or 78%-87%of the weight of the pharmaceutical composition.
In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 2: 3, 2: 1, 1: 1, 2.5: 1, 3.5: 1, 4: 1 or 5: 1.
In some embodiments, the combination of mannitol and microcrystalline cellulose of the present invention, calculated as a percentage by weight, accounts for 10%-90%, 54%-87%, or 74%-77%of the weight of the pharmaceutical composition.
In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 1, 1: 2, 2: 3, 1: 3, 1: 4, 2: 1, 2: 5, 3: 1, 4: 1 or 5: 1.
In some embodiments, the combination of mannitol and pregelatinized starch of the present invention, calculated as a percentage by weight, accounts for 10%-90%or 79%-87%of the weight of the pharmaceutical composition.
In some embodiments, the weight ratio of mannitol to pregelatinized starch of the present invention is 1: 5-5: 1. In some embodiments, the weight ratio of mannitol to pregelatinized starch of the present invention is 2: 3.
In some embodiments, the combination of lactose, microcrystalline cellulose and pregelatinized starch, calculated as a percentage by weight, accounts for 15%-90%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition.
In other embodiments, the combination of lactose, microcrystalline cellulose and pregelatinized starch, calculated as a percentage by weight, accounts for 75%-85%or 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition.
In some embodiments, the disintegrant (s) of the present invention (e.g.., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof) , calculated as a percentage by weight, account (s) for 0-15%, 1%-15%, 2%-15%or 1%-5%of the weight of the pharmaceutical composition.
In some embodiments, the sodium lauryl sulfate of the present invention, calculated as a percentage by weight, accounts for 0-15%, 0-8%, 0.5%-15%or 0.5%-8%of the weight of the pharmaceutical composition.
In some embodiments, the magnesium stearate of the present invention, calculated as a percentage by weight, accounts for 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition.
In some embodiments, the micronized silica gel of the present invention, calculated as a percentage by weight, accounts for 0.5%-10%or 0.5%-8%of the total weight of the pharmaceutical composition.
In some embodiments, the hydroxypropyl methylcellulose of the present invention, calculated as a percentage by weight, accounts for 0-20%, 0-3%or 0.5%-5%of the total weight of the pharmaceutical composition.
In some embodiments, the combination of lactose and microcrystalline cellulose of the present invention, calculated as a percentage by weight, accounts for 15%-87%, 15%-85%, 75%-86%or 79%-80%of the weight of the pharmaceutical composition.
In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 1: 3-5: 1. In some embodiments, the weight ratio of lactose to microcrystalline cellulose of the present invention is 2: 1, 1: 1, 2.5: 1, 3.5: 1, 4: 1, or 5: 1.
In some embodiments, the combination of mannitol and microcrystalline cellulose of the present invention, calculated as a percentage by weight, accounts for 15%-87%, 15%-85%or 54%-87%of the weight of the pharmaceutical composition.
In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 3-5: 1. In some embodiments, the weight ratio of mannitol to microcrystalline cellulose of the present invention is 1: 1, 1: 1.5, 1: 2, 2: 1, or 3: 1.
In some embodiments, the combination of mannitol and pregelatinized starch of the present invention, calculated as a percentage by weight, accounts for 15%-87%, 15%-85%or 79%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of mannitol to pregelatinized starch is 1: 1.5 (i.e., 2: 3) .
In some embodiments, the combination of lactose, microcrystalline cellulose and pregelatinized starch of the present invention, calculated as a percentage by weight, accounts for 15%-85%of the weight of the pharmaceutical composition; wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1.
In some embodiments, the combination of lactose, microcrystalline cellulose and pregelatinized starch of the present invention, calculated as a percentage by weight, accounts for 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 9.5%-10.5%of the weight of the pharmaceutical composition; wherein the weight ratio of lactose to microcrystalline cellulose is 4: 1.
In some embodiments, the disintegrant (s) of the present invention (e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof) , calculated as a percentage by weight, account (s) for 2%-15%or 2%-4%of the weight of the pharmaceutical composition. In some embodiments, the disintegrant (s) of the present invention (e.g., croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof) , calculated as a percentage by weight, account (s) for 2%, 3%, 4%, 5%, 10%or 15%of the weight of the pharmaceutical composition.
In some embodiments, the sodium lauryl sulfate of the present invention, calculated as a percentage by weight, accounts for 0-15%, 0-8%, 0.5%-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition. In some embodiments, the sodium lauryl sulfate of the present invention, calculated as a percentage by weight, accounts for 0.5%, 0.75%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 8%, 10%or 15%of the weight of the pharmaceutical composition.
In some embodiments, the magnesium stearate of the present invention, calculated as a percentage by weight, accounts for 0.5%-8%, 0.5%-5%or 0.5%-2%of the weight of the pharmaceutical composition. In some embodiments, the magnesium stearate of the present invention, calculated as a percentage by weight, accounts for 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 5%, 6%, 7%or 8%of the weight of the pharmaceutical composition.
In some embodiments, the micronized silica gel of the present invention, calculated as a percentage by weight, accounts for 0.5%-10%, 0.5%-5%or 0.5%-2%of the total weight of the pharmaceutical composition. In some embodiments, the micronized silica gel of the present invention, calculated as a percentage by weight, accounts for 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%or 10%of the total weight of the pharmaceutical composition.
In some embodiments, the hydroxypropyl methylcellulose of the present invention, calculated as a percentage by weight, accounts for 0-20%, 0-10%or 1%-5%of the total weight of the pharmaceutical composition. In some embodiments, the hydroxypropyl methylcellulose of the present invention, calculated as a percentage by weight, accounts for 1%, 2%, 3%, 4%, 5%, 10%, 15%or 20%of the total weight of the pharmaceutical composition.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers, wherein the filler (s) , calculated as a percentage by weight, account (s) for 15%-85%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition; wherein,
the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1; or
the filler is a combination of mannitol and microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1; or
the filler is a combination of mannitol and pregelatinized starch, and the weight ratio of mannitol to pregelatinized starch is 1: 1.5; or
the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%, 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%, 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%, 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1;
c) optionally, one or more disintegrants, wherein the disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof, and the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition;
d) optionally, one or more surfactants, wherein the surfactant includes but is not limited to sodium lauryl sulfate; optionally, the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition;
e) optionally, one or more lubricants, wherein the lubricant includes but is not limited to magnesium stearate; optionally, the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-3%or 0.5%-2%of the weight of the pharmaceutical composition; and
f) optionally, one or more glidants, wherein the glidant includes but is not limited to micronized silica gel; optionally, the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition.
In some embodiments, the pharmaceutical composition of the present invention comprises:
a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,
b) one or more fillers, wherein the filler (s) , calculated as a percentage by weight, account (s) for 15%-85%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition; wherein,
the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1; or
the filler is a combination of mannitol and microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1; or
the filler is a combination of mannitol and pregelatinized starch, and the weight ratio of mannitol to pregelatinized starch is 1: 1.5; or
the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1;
c) optionally, one or more disintegrants, wherein the disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof, and the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition;
d) optionally, one or more surfactants, wherein the surfactant includes but is not limited to sodium lauryl sulfate; optionally, the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition;
e) optionally, one or more lubricants, wherein the lubricant includes but is not limited to magnesium stearate; optionally, the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-3%or 0.5%-2%of the weight of the pharmaceutical composition;
f) optionally, one or more glidants, wherein the glidant includes but is not limited to micronized silica gel; optionally, the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition;
g) optionally, one or more binders, wherein the binder includes but is not limited to hydroxypropyl methylcellulose; optionally, the hydroxypropyl methylcellulose, calculated as a percentage by weight, accounts for 1%-5%of the total weight of the pharmaceutical composition.
In other embodiments, the combination of lactose, microcrystalline cellulose and pregelatinized starch, calculated as a percentage by weight, accounts for 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 9.5%-10.5%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 4: 1.
In some embodiments, the pharmaceutical composition of the present invention is a solid pharmaceutical preparation.
In some embodiments, the solid pharmaceutical preparation is a powder, granule, tablet, capsule or pill.
In some embodiments, the pharmaceutical composition of the present invention is administered once, twice, three times or four times a day.
In some embodiments, the pharmaceutical composition of the present invention further comprises other additional therapeutic agents, wherein the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an anti-hyperglycemic agent, an anti-obesity drug, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or any combination thereof.
In some embodiments, the anti-diabetic agent other than an SGLT-2 inhibitor or anti-hyperglycemic agent is independently a biguanide drug, a sulfonylurea drug, a glucosidase inhibitor, a PPAR agonist (peroxisome proliferator activated receptor agonist) , an αP2 inhibitor (adipocyte fatty acid binding protein inhibitor) , a PPARα/γ dual agonist (peroxisome proliferator activated receptor α/γ dual activator) , a dipeptidyl peptidase IV (DPP-IV) inhibitor, a glinide drug, insulin, a glucagon-like peptide-1 (GLP-1) inhibitor, a PTP1B inhibitor (protein tyrosine phosphatase 1B inhibitor) , a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor or any combination thereof.
In some embodiments, the lipid-lowering agent is an MTP inhibitor (microsomal triglyceride transfer protein inhibitor) , an HMGCoA reductase inhibitor (hydroxymethylglutaryl coenzyme A reductase inhibitor) , a squalene synthase inhibitor, a butyric acid-based lipid-lowering drug, an ACAT inhibitor (acetylcholesterol acetyltransferase inhibitor) , a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na (+) /bile acid cotransporter inhibitor, an upregulator of LDL receptor activity (up-regulator of low-density lipoprotein receptor activity) , niacin-like lipid-lowering drugs (such as niacin or a derivative thereof) , a bile acid sequestrant or any combination thereof.
In some embodiments, the lipid-lowering agent is pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, rosuvastatin or any combination thereof.
In other aspect, provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting SGLT-2.
In other aspect, provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting SGLT-1.
In other aspect, provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for increasing the level of high-density lipoprotein.
In other aspect, provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
In one aspect, provided herein is the pharmaceutical composition disclosed herein for use in inhibiting SGLT-2.
In other aspect, provided herein is the pharmaceutical composition disclosed herein for use in inhibiting SGLT-1.
In one aspect, provided herein is the pharmaceutical composition disclosed herein for use in increasing the level of high-density lipoprotein.
In other aspect, provided herein is the pharmaceutical composition disclosed herein for use in preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
In one aspect, provided herein is a method of inhibiting SGLT-2 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
In other aspect, provided herein is a method of inhibiting SGLT-1 in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
In one aspect, provided herein is a method of increasing the level of high-density lipoprotein in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
In other aspect, provided herein is a method of preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein, wherein the disease is diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.
In other aspect, the present invention also provides a method for preparing the pharmaceutical composition, which is simple and easy to implement, has good stability and high safety, and is suitable for industrial production.
The present invention provides a method for preparing the pharmaceutical composition of the present invention, comprising the following steps: a compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and one or more pharmaceutically acceptable adjuvants of the present invention are mixed together in any desired order to form a total mixed powder, and the required amount of the total mixed powder is filled into capsules or formed into tablets.
The method for forming tablets according to the present invention includes but is not limited to the method of wet granulation, dry granulation or direct powder compression.
In some embodiments, the present invention relates to a method for preparing the pharmaceutical composition, comprising the following steps:
1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants, binders and glidants, are mixed uniformly to obtain a premix;
2) optionally, the lubricants and the premix are mixed uniformly to obtain a total mixed powder; and
3) the total mixed powder is filled into suitable hollow capsules.
In some embodiments, the present invention relates to a preparation method of the pharmaceutical composition, comprising the following steps:
1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants, binders and glidants, are mixed uniformly to obtain a premix;
2) optionally, the lubricants and the premix are mixed uniformly to obtain a total mixed powder; and
3) the total mixed powder is compressed into tablets to obtain plain tablets.
In some embodiments, the present invention relates to a preparation method of the pharmaceutical composition, comprising the following steps:
1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants and binders, are subjected to wet granulation and drying to obtain dry particles;
2) the lubricants, glidants and dry particles are mixed uniformly to obtain a total mixed powder; and
3) the total mixed powder is compressed into tablets to obtain plain tablets.
In some embodiments, the preparation method of the pharmaceutical composition of the present invention further comprises the following step: coating plain tablets to obtain coated tablets.
The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
The present invention relates to a pharmaceutical composition comprising a compound having formula (I) , (II) , (I-A) and/or (II-A) or a pharmaceutically acceptable salt, a solvate or a complex thereof, and a method for preparing the pharmaceutical composition, and also relates to the pharmaceutical application of the pharmaceutical composition.
DEFINITIONS AND GENERAL TERMINOLOGY
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term “optionally” or “optional” means that the subsequently described event or condition can but does not necessarily occur, and the description includes the case where the event or condition occurs, and the case where the event or condition does not occur.
The phrase “pharmaceutically acceptable” refers to that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising a formulation, and/or the mammal being treated therewith. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term “pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.
The term “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid, ethanolamine, etc.
The term “hydrate” refers to the complex where the solvent molecule is water.
The term “pharmaceutically acceptable adjuvant” refers to the excipients and additives used in the production of medicines and formulating prescriptions. In addition to the active ingredients, they have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations. Common pharmaceutically acceptable adjuvants include, but are not limited to, filler, wetting agent, lubricant, glidant, surfactant, binder, disintegrant, coating agent, flavoring agent, film-forming agent, antioxidant, protective agent, solvent, propellant, solubilizer, cosolvent, emulsifier, coloring agent, osmotic pressure regulator, stabilizer, plasticizer, anti-adhesive, anti-caking agent, pressure aid, bacteriostatic agent, pH regulator, etc.
The term “comprise” , “include” or “contain” is an open expression, and means comprising the contents disclosed herein, but don’t exclude other contents.
The term “specification” refers to the weight (or potency) or content (%) or volume of the main drug contained in each unit preparation.
The term “treatment” is meant to include preventing, alleviating, stopping or reversing the progress and severity of the condition and symptoms being treated. Therefore, the present invention includes medical treatment and/or prophylactic administration.
The term “effective amount” refers to the amount of a pharmaceutical preparation that is effective for the treatment of conditions and symptoms.
The “subject” in the present invention refers to an animal who can benefit from the pharmaceutical composition and/or treatment method of the present invention, preferably a mammal, more preferably a primate including lower primates and more preferably a human. A subject, whether it is a human or non-human animal, can be referred to as an individual, patient, animal, host, or recipient.
Unless otherwise specified, “equivalent amount” refers to an equivalent molar amount, for example, “an equivalent amount of compound having formula (II-A) ” in “the complex having formula (II) or an equivalent amount of compound having formula (II-A) is weighed” means that the molar amount of the compound having the formula (II-A) is the same as the molar amount of the compound having the formula (II) , that is, the mass of the drug molecule (i.e., the compound having the formula (I) ) in the two is the same.
In the present invention, regardless of whether or not the word “about” or “approximately” is used, all numbers disclosed herein are approximate values. The value of each number may vary by less than 10%, or a reasonable difference that one skilled in the art would consider, such as 1%, 2%, 3%, 4%, or 5%.
In the present invention, unless otherwise specified, the numerical range from N
1 to N
2, N
1-N
2 or N
1~N
2 means that the range includes the endpoints N
1 and N
2 and any numerical value in the interval, for example, the numerical range 1~5 means that the range includes 1, 5, and any number between 1 and 5.
EXAMPLES
In the pharmaceutical composition of the present invention, the active ingredient may be the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof. Those skilled in the art should recognize that although in specific embodiments, the active ingredient is a complex having formula (I-A) , (II-A) or (II) , it can be replaced by a compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof, and the corresponding amount can be converted after measuring the water content. In some embodiments, the mass of the compound having formula (I) is theoretically 77.74%of the mass of the compound having formula (I-A) . In some embodiments, the mass of the compound having formula (I) is theoretically 74.83%-75.40%of the mass of the compound having formula (II-A) . In some embodiments, when x is 1.25, the mass of the compound having formula (I) is theoretically 74.83%of the mass of the compound having formula (II-A) ; in some embodiments, when x is 1, the mass of the compound having formula (I) is theoretically 75.40%of the mass of the compound having formula (II-A) .
Preparation Examples
Example 1 The formulation and preparation process of capsules containing different proportions of fillers
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
1) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , mannitol, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, micronized silica gel and magnesium stearate were weighed respectively according to the formulation table;
2) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , mannitol, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium and micronized silica gel were sieved together, and the sieved powder was put into a mixing hopper for mixing. The rotation speed of the mixing hopper was 10 rpm and the premixing time was 15-30 min to obtain a premix;
3) The magnesium stearate and the premix were mixed and sieved, and then added to the mixing hopper for total mixing. The total mixing time was 3-7 min to obtain a total mixed powder;
4) The total mixed powder was filled into suitable hollow gelatin capsules and packaged.
Example 2 The formulation and preparation process of capsules containing different proportions of surfactants
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 03-05, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 3 The formulation and preparation process of capsules containing different proportions of disintegrants
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 06-07, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 4 The formulation and preparation process of capsules containing different proportions of glidants
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 08-09, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 5 The formulation and preparation process of capsules containing different proportions of lubricants
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 10-11 and 46, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 6 The formulation and preparation process of capsules containing different proportions of fillers
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 12-13, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 7 The formulation and preparation process of capsules containing different proportions of surfactants
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 14-16, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 8 The formulation and preparation process of capsules containing different proportions of disintegrants
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 17-18, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 9 The formulation and preparation process of capsules containing different proportions of glidants
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 19-20, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 10 The formulation and preparation process of capsules containing different proportions of lubricants
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 21-22, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 11 The formulation and preparation process of capsules containing different types of fillers
Wherein, the content of the compound having formula (I) in each capsule is 5 mg.
Preparation process:
According to the formulation of Samples 23-25, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 12 The formulation and preparation process of capsules containing different types of fillers
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 26-28, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 13 The formulation and preparation process of other capsules
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 46 and 47, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 14 The formulation and preparation process of other capsules
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 48-50, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 15 The formulation and preparation process of other capsules
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 51 and 52, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 16 The formulation and preparation process of other capsules
Wherein, the content of the compound having formula (I) in each capsule is 50 mg.
Preparation process:
According to the formulation of Samples 53 and 54, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 17 The formulation and preparation process of other capsules
Wherein, the content of the compound having formula (I) is 50 mg.
Preparation process:
According to the formulation of Samples 55 and 56, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 18 The formulation and preparation process of capsules with different particle sizes
According to the following formulation, referring to the preparation method of Example 1, capsules containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared by using active ingredients of different particle sizes, as shown in Samples 57-62.
Formulation: compound having formula (II-A) 66.84 mg, mannitol 111.26 mg, microcrystalline cellulose 166.90 mg, croscarmellose sodium 11.25 mg, sodium lauryl sulfate 3.75 mg, micronized silica gel 3.75 mg, magnesium stearate 11.25 mg.
Example 19 The formulation and preparation process of tablets containing the compound having formula (I) or the complex having formula (II)
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
1) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, micronized silica gel and magnesium stearate were weighed respectively according to the formulation table;
2) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium and micronized silica gel were sieved together, and the sieved powder was put into a mixing hopper for mixing. The rotation speed of the mixing hopper was 10 rpm and the premixing time was 15-30 min to obtain a premix;
3) The magnesium stearate and the premix were mixed and sieved, and then added to the mixing hopper for total mixing. The total mixing time was 3-7 min to obtain a total mixed powder;
4) the total mixed powder was compressed into tablets and packaged.
Example 20 The formulation and preparation process of tablets containing different proportions of fillers
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
According to the formulation of Samples 30-32, referring to the preparation method of Example 19, tablets containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 21 The formulation and preparation process of tablets containing different proportions of fillers
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
1) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, sodium lauryl sulfate, croscarmellose sodium, micronized silica gel and magnesium stearate were weighed respectively according to the formulation table of Samples 33-35;
2) The complex having formula (II) or an equivalent amount of the compound having formula (I) or the complex having formula (II-A) , mannitol, microcrystalline cellulose, sodium lauryl sulfate, hydroxypropyl methylcellulose and croscarmellose sodium were subjected to wet granulation and drying to obtain dry particles;
3) The magnesium stearate, micronized silica gel and dry particles were mixed and sieved, and then added to a mixing hopper for total mixing. The total mixing time was 3-7 min to obtain a total mixed powder;
4) the total mixed powder was compressed into tablets and packaged.
Example 22 The formulation and preparation process of tablets containing different proportions of fillers
Table 22-A
Table 22-B
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
According to the formulation of Samples 36-40, referring to the preparation method of Example 19, tablets containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 23 The formulation and preparation process of tablets containing different types of disintegrants
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
According to the formulation of Samples 41-42, referring to the preparation method of Example 19, tablets containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Example 24 The formulation and preparation process of tablets containing different proportions of surfactants and/or lubricants
Wherein, the content of the compound having formula (I) in each tablet is 50 mg.
Preparation process:
According to the formulation of Samples 43-45, referring to the preparation method of Example 19, tablets containing the compound having formula (I) or the complex having formula (II) or formula (II-A) were prepared.
Test Example
1. Determination of the dissolution in vitro of the pharmaceutical composition of the present invention
Purpose: to determine the dissolution in vitro of the pharmaceutical composition of the present invention.
Test materials:
Instruments: dissolution apparatus, high performance liquid chromatography (HPLC) , one hundred thousandth electronic balance;
Reagents: sodium acetate trihydrate (analytical grade) , glacial acetic acid (analytical grade) , acetonitrile (chromatographic grade) , ultrapure water;
Reference sample: the complex having formula (II) .
Test method:
1. Dissolution conditions
Medium: pH 4.5 acetate buffer
Volume of the medium: 900±9 mL
Dissolution method: the capsule adopted the paddle method combined with the sedimentation basket, and the tablet adopted the paddle method
Speed: 75 rpm
Temperature of the medium: 37±0.5℃
Sampling position: at the top of the blade to the midpoint of the liquid surface, and 10 mm away from the vessel wall
Volume of sampling liquid: 5 mL
Sampling time: 30 min.
2. Solution preparation:
Dissolution medium: to a mixture of 2.99 g of sodium acetate trihydrate and 1.85 mL of glacial acetic acid was added purified water to a volume of 1000 mL. The mixture was stirred and dissolved completely, then glacial acetic acid was added to adjust the pH to 4.5. The resulting mixture was ready for use.
Mobile phase A: 350 mL of acetonitrile and 650 mL of ultrapure water were mixed thoroughly, and ultrasonically degassed for 10 min. The resulting mixture was ready for use.
Diluent: 500 mL of dissolution medium was filtered through a filter membrane, then 425 mL of filtrate and 75 mL of acetonitrile were added. The mixture was mixed thoroughly and ready for use.
Blank solution: 5 mL of dissolution medium was filtered through membrane, 2 mL of the initial filtrate was discarded, and the subsequent filtrate was taken and ready for use.
Reference sample stock solution: the complex having formula (II) (calculated by the compound having formula (I) , approximately 28 mg) was taken and accurately weighed, then placed in a 100 mL volumetric flask. 15 mL of acetonitrile was added to dissolve the solid completely, then about 65 mL of the dissolution medium filtered through the filter membrane was added. After 5 minutes of sonication, the mixture was diluted to the mark with the dissolution medium filtered through the filter membrane, and shaken thoroughly to obtain the reference sample stock solution. Two copies of the reference sample stock solution in parallel were prepared.
Reference sample solution: 2 mL each of the above reference sample stock solution was accurately measured, diluted with the diluent, and shaken thoroughly to prepare reference sample solutions containing about 0.0056 mg/mL, 0.0112 mg/mL, 0.0224 mg/mL, and 0.056 mg/mL of the compound having formula (I) respectively.
Test sample solution: 5 mL of the dissolution solution of the pharmaceutical composition of the present invention was taken at a specified time point, and quickly filtered with a filter membrane. 2 mL of the initial filtrate was discarded, and the subsequent filtrate was taken and ready for use.
3. Detection conditions:
Instrument: high performance liquid chromatography;
Chromatographic column: Agilent ZORBAX Eclipse plus C18, 4.6×150mm, 5 μm (or other applicable chromatographic column) ;
Detector: UV detector, detection wavelength: 225 nm;
Flow rate: 1.0 mL/min;
Column temperature: 35℃;
Injection volume: 50 μL;
Mobile phase: acetonitrile: mobile phase A=15: 85;
Running time: 8 min.
4. Detection
One injection of the test sample solution was taken and the chromatogram was recorded. The accompanying control was used during the injection process, that is, before the injection and after each injection of the test sample solution for about 4 hours, one injection of the reference sample solution was taken, and the samples were injected in sequence. At the end of the experiment, one injection of the reference sample solution was taken. The first 5 injections of the first reference sample solution and 1 injection of the accompanying control were used to calculate the RSD of the main peak area, which should not be greater than 2.0%; if there were multiple accompanying controls, the same method was used to calculate. The injection sequence is as shown in the table below.
Name | Number of injections |
Blank solution | 1-2 |
Reference sample solution | 6 |
Reference sample solution | 2 |
Reference sample solution | 1 |
Test sample solution | 1 |
… | … |
Reference sample solution | 1 |
… | … |
Reference sample solution | 1 |
5. Calculation
The dissolution of test sample (capsule or tablet) of the complex having formula (II) was calculated according to the following formula:
wherein:
W
S1: The weighing amount of the reference sample solution, mg;
P: The percentage of the reference sample, based on C
23H
27ClO
7·C
5H
7NO
3, %;
A
X: The peak area of the test sample solution;
A
S1: The average peak area of the reference sample solution (1 injection before and after the test sample solution) ;
D
S1: Dilution factor of the reference sample solution, mL;
D
X: Dilution factor of the test sample solution, mL;
L: The labeled amount of the test sample of the complex having formula (II) , based on C
23H
27ClO
7, mg;
0.7774: The ratio of the molecular mass of C
23H
27ClO
7 to C
23H
27ClO
7·C
5H
7NO
3.
6. Test results
Table A The dissolution in vitro of the pharmaceutical composition of the present invention (unit: %)
Sample number | 5 min | 10 min | 15 min | 30 min | 45 min | 60 min |
Sample 01 | 64±6.72 | 89±3.27 | 96±2.74 | 100±3.01 | 100±2.71 | 100±1.72 |
Sample 02 | 73±5.09 | 90±3.03 | 95±2.28 | 98±1.90 | 98±2.10 | 97±2.04 |
Sample 03 | 55±6.28 | 84±2.04 | 93±1.21 | 101±1.97 | 102±1.38 | 102±0.98 |
Sample 04 | 59±6.29 | 86±2.13 | 93±1.89 | 98±1.66 | 99±1.22 | 100±2.00 |
Sample 05 | 68±8.60 | 89±4.60 | 96±4.54 | 98±3.21 | 100±2.79 | 100±1.98 |
Sample 06 | 58±5.50 | 81±3.39 | 89±3.08 | 95±2.43 | 95±1.97 | 96±2.07 |
Sample 07 | 61±4.72 | 84±2.28 | 91±1.67 | 97±1.37 | 98±1.05 | 97±2.25 |
Sample 08 | 56±8.43 | 81±5.36 | 88±3.42 | 94±2.39 | 95±1.89 | 96±1.34 |
Sample 09 | 66±5.06 | 87±3.52 | 91±2.72 | 95±2.48 | 95±1.87 | 95±2.22 |
Sample 10 | 66±4.35 | 86±1.41 | 92±0.73 | 96±0.70 | 97±0.89 | 97±1.18 |
Sample 11 | 66±2.80 | 86±1.63 | 92±1.71 | 97±1.62 | 98±1.57 | 98±1.36 |
Sample 12 | 74±4.85 | 90±3.56 | 93±2.66 | 95±1.64 | 95±1.64 | 94±1.17 |
Sample 13 | 82±3.37 | 93±1.03 | 95±1.60 | 97±2.04 | 97±1.60 | 97±2.04 |
Sample 14 | 69±6.08 | 85±6.45 | 89±6.56 | 93±4.58 | 94±4.13 | 95±3.20 |
Sample 15 | 69±3.91 | 85±3.19 | 90±3.27 | 92±2.31 | 94±3.25 | 94±2.58 |
Sample 16 | 77±3.49 | 91±3.41 | 94±2.54 | 98±2.29 | 98±1.87 | 99±2.00 |
Sample 17 | 78±2.94 | 91±3.22 | 95±2.26 | 98±2.99 | 98±2.48 | 98±2.42 |
Sample number | 5 min | 10 min | 15 min | 30 min | 45 min | 60 min |
Sample 18 | 78±3.27 | 89±1.76 | 93±2.25 | 96±2.13 | 97±1.87 | 98±2.74 |
Sample 19 | 78±2.50 | 90±2.66 | 94±3.19 | 98±2.14 | 100±2.26 | 100±1.72 |
Sample 20 | 78±3.67 | 90±1.82 | 94±1.86 | 97±1.47 | 98±0.66 | 98±1.53 |
Sample 21 | 77±3.54 | 90±3.61 | 95±3.78 | 98±3.08 | 99±2.07 | 99±1.83 |
Sample 22 | 79±3.01 | 93±1.83 | 96±1.63 | 99±1.26 | 100±0.98 | 100±0.98 |
Sample 23 | 82±3.37 | 93±1.03 | 95±1.60 | 97±2.04 | 97±1.60 | 97±2.04 |
Sample 24 | 79±6.29 | 94±6.41 | 97±5.46 | 99±2.71 | 98±2.40 | 99±1.51 |
Sample 25 | 78±2.66 | 95±2.26 | 97±1.79 | 98±2.07 | 99±1.97 | 99±2.34 |
Sample 26 | 73±5.09 | 90±3.03 | 95±2.28 | 98±1.90 | 98±2.10 | 97±2.04 |
Sample 27 | 58±6.09 | 91±1.87 | 97±1.21 | 100±1.21 | 99±1.79 | 98±0.89 |
Sample 28 | 51±10.46 | 81±6.28 | 91±3.44 | 97±1.67 | 97±1.63 | 98±1.22 |
Sample 29 | 54±4.13 | 75±2.16 | 81±1.72 | 87±1.63 | 88±1.87 | 88±1.87 |
Sample 31 | 61±1.37 | 79±1.64 | 88±1.64 | 94±2.14 | 94±2.88 | 94±2.66 |
Sample 32 | 54±3.51 | 75±2.80 | 86±3.19 | 95±3.44 | 98±3.08 | 98±1.63 |
Sample 33 | 63±30.76 | 91±1.33 | 94±1.21 | 96±0.82 | 96±0.98 | 96±1.21 |
Sample 34 | 62±7.03 | 84±3.27 | 88±3.54 | 93±3.13 | 94±2.88 | 96±2.37 |
Sample 35 | 66±1.94 | 78±1.03 | 83±1.03 | 86±1.55 | 88±1.76 | 88±1.67 |
Sample 37 | 38±2.31 | 62±3.51 | 80±2.89 | 93±2.08 | 97±1.00 | 98±0.58 |
Sample 38 | 38±6.51 | 64±5.51 | 85±3.61 | 98±2.08 | 101±1.15 | 101±1.15 |
Sample 39 | 66±5.28 | 85±5.56 | 90±4.26 | 95±2.45 | 96±2.28 | 97±1.97 |
Sample 40 | 39±7.02 | 77±5.69 | 93±3.51 | 98±2.08 | 99±2.52 | 100±2.08 |
Sample 44 | 65±5.33 | 83±5.40 | 89±3.99 | 93±2.45 | 94±2.28 | 95±1.60 |
Sample 45 | 62±10.97 | 85±1.00 | 90±0.58 | 93±0.58 | 94±1.00 | 93±0.58 |
Sample 46 | 78±10.57 | 92±3.25 | 93±2.71 | 94±2.00 | 94±2.00 | 94±2.00 |
Sample 47 | 78±8.38 | 94±3.76 | 96±3.35 | 97±2.61 | 98±2.58 | 98±2.10 |
Sample 48 | 15±7.89 | 55±6.02 | 85±5.15 | 99±0.52 | 100±0.75 | 100±0.63 |
Sample 49 | 63±10.33 | 84±3.88 | 91±0.98 | 93±0.63 | 94±0.82 | 95±0.52 |
Sample 50 | 54±6.54 | 86±2.16 | 92±1.47 | 95±1.94 | 96±3.20 | 97±1.76 |
Sample 51 | 60±5.34 | 86±1.97 | 93±2.25 | 98±0.89 | 97±0.75 | 96±0.82 |
Sample 52 | 52±4.22 | 77±4.76 | 89±1.52 | 94±1.21 | 94±1.26 | 94±1.17 |
Sample 53 | 63±4.64 | 85±2.58 | 92±1.86 | 97±1.33 | 98±1.05 | 98±1.33 |
Sample 54 | 46±6.09 | 67±4.88 | 80±4.17 | 94±3.01 | 97±1.17 | 98±1.10 |
Sample 55 | 16±5.19 | 50±11.44 | 72±9.83 | 85±3.61 | 89±2.64 | 92±2.64 |
Sample 56 | 43±3.49 | 62±1.86 | 69±1.33 | 79±1.60 | 84±0.98 | 87±1.63 |
Sample 57 | 54±4.02 | 77±2.23 | 85±1.72 | 93±1.79 | 95±1.60 | 95±1.21 |
Sample 58 | 58±3.63 | 75±2.07 | 81±1.47 | 88±1.37 | 90±0.98 | 92±1.17 |
Sample 59 | 54±5.31 | 80±3.44 | 90±1.52 | 97±1.38 | 98±1.21 | 98±1.47 |
Sample number | 5 min | 10 min | 15 min | 30 min | 45 min | 60 min |
Sample 60 | 59±4.43 | 84±1.86 | 92±1.63 | 96±1.37 | 97±1.05 | 97±1.33 |
Sample 61 | 33±7.69 | 75±2.79 | 89±1.26 | 99±1.47 | 101±0.84 | 101±1.38 |
Sample 62 | 78±10.57 | 92±3.25 | 93±2.71 | 94±2.00 | 94±2.00 | 94±2.00 |
The test results show that basically, the dissolution in vitro of the pharmaceutical composition of the present invention after 30 minutes is greater than 80% (acceptance standard: the dissolution after 30 minutes is not less than 80%) .
The dissolution of the pharmaceutical compositions comprising active ingredients with different particle sizes was also determined in the present invention. From the dissolution data of Samples 57-62, it can be seen that the particle size of the active ingredient affects the dissolution of the pharmaceutical composition: when the particle size D90 of the active ingredient is about 61 μm, the dissolution of the pharmaceutical composition at 30 minutes is about 79%; and when the particle size D90 of the active ingredient is less than 61 μm, the dissolution of the pharmaceutical composition at 30 minutes is greater than 80%.
2. Determination of the content uniformity of the pharmaceutical composition of the present invention
Purpose: to determine the content uniformity of the pharmaceutical composition of the present invention.
Test materials:
Instruments: high performance liquid chromatography (HPLC) , one hundred thousandth electronic balance;
Reagents: ultrapure water, acetonitrile (chromatographically pure) ;
Reference sample: the complex having formula (II) .
Test method:
1. Solution preparation:
Blank solution/diluent: 600 mL of acetonitrile and 400 mL of ultrapure water were mixed and shaken thoroughly for use.
Mobile phase A: 350 mL of acetonitrile and 650 mL of ultrapure water were mixed thoroughly, and ultrasonically degassed for 10 min. The resulting mixture was ready for use.
Reference sample solution: the complex having formula (II) (calculated by the compound having formula (I) , approximately 20 mg) was taken and accurately weighed, then placed in a 100 mL volumetric flask. 80 mL of the diluent was added, and the mixture was sonicated for 10 min to completely dissolve the solid. Then the mixture was diluted to the mark with the diluent, and shaken thoroughly to prepare a reference sample solution containing about 0.2 mg/mL of the compound having formula (I) . Two copies of the reference sample solution in parallel were prepared.
Test sample solution: one capsule prepared by the present invention was taken, the capsule shell was open, and the contents were poured out. The contents together with the capsule shell were placed in a volumetric flask, or one tablet prepared by the present invention was placed it in a volumetric flask, then diluted with diluent, shaken thoroughly to prepare a test sample solution containing about 0.2 mg/mL of the compound having formula (I) ; 10 copies of the test sample solution in parallel were prepared.
2. Detection conditions
Instrument: high performance liquid chromatography;
Chromatographic column: Agilent ZORBAX Eclipse plus C18, 4.6×150 mm, 5 μm (or other suitable chromatographic column) ;
Detector: UV detector, detection wavelength: 225 nm;
Flow rate: 1.0 mL/min;
Column temperature: 35℃;
Injection volume: 10 μL;
Mobile phase: acetonitrile: mobile phase A=15: 85;
Running time: 8 min.
3. Detection
One injection of each test sample solution was taken and the chromatogram was recorded. The accompanying control was used during the injection process, that is, before the injection and after each injection of the test sample solution for about 4 hours, one injection of the reference sample solution was taken, and the samples were injected in sequence. At the end of the experiment, one injection of the reference sample solution was taken. if there were multiple accompanying controls, the same method was used to calculate. The injection sequence is as shown in the table below.
Sample name | Number of injections |
Blank solution | 1-2 |
Reference sample solution | 6 |
Reference sample solution | 2 |
Reference sample solution | 1 |
Test sample solution | 1 |
··· | ··· |
Reference sample solution | 1 |
··· | ··· |
Reference sample solution | 1 |
4. Calculation
The content uniformity of the composition containing the complex having formula (II) was calculated according to the following formula:
wherein:
W
S1: The weighing amount of the reference sample solution, mg;
A
S1: The average peak area of the reference sample solution (1 injection before and after the test sample solution) ;
A
x: The peak area of the test sample solution;
D
X: Dilution factor of the test sample solution, mL;
D
S: Dilution factor of the reference sample solution, mL;
L: The labeled amount of test sample (capsule or tablet) of the complex having formula (II) , based on C
23H
27ClO
7, mg;
P: The percentage of the reference sample, based on C
23H
27ClO
7·C
5H
7NO
3, %;
0.7774: The ratio of the molecular mass of C
23H
27ClO
7 to C
23H
27ClO
7·C
5H
7NO
3;
X
i: The relative content of each capsule/tablet with a labeled amount of 100;
Mean value, that is, the average relative content of each capsule/tablet with a labeled amount of 100;
n: The number of test sample;
A: The absolute value of the difference between the labeled amount and the mean value;
S: Standard deviation.
5. Test results
The test results show that the content uniformity of the pharmaceutical compositions of the present invention meets the regulations of the 2015 edition of the Chinese Pharmacopoeia.
Reference throughout this specification to “an embodiment” , “some embodiments” , “one embodiment” , “another example” , “an example” , “a specific example” , or “some examples” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments” , “in one embodiment” , “in an embodiment” , “in another example” , “in an example” , “in a specific example” , or “in some examples” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.
Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.
Claims (52)
- The pharmaceutical composition of claim 1, wherein the specification of the pharmaceutical composition is 5 mg -50 mg.
- The pharmaceutical composition of claim 1 or 2, further comprising:b) one or more fillers.
- The pharmaceutical composition of any one of claims 1 to 3, wherein the complex is a complex formed by the compound having formula (I) and L-pyroglutamic acid, and the molar ratio of the compound having formula (I) to L-pyroglutamic acid is 1: 1.
- The pharmaceutical composition of claim 4, wherein the complex is a hydrate.
- The pharmaceutical composition of any one of claims 3 to 6, wherein the filler is corn starch, lactose, microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, starch, glucose, fructose, xylitol, sorbitol, calcium carbonate, calcium sulfate, dextrin, maltodextrin, maltitol or any combination thereof.
- The pharmaceutical composition of any one of claims 3 to 7, wherein the filler is a combination of lactose and microcrystalline cellulose, a combination of mannitol and microcrystalline cellulose, a combination of mannitol and pregelatinized starch, or a combination of lactose, microcrystalline cellulose and pregelatinized starch.
- The pharmaceutical composition of any one of claims 1 to 8, further comprising:d) optionally one or more surfactants.
- The pharmaceutical composition of any one of claims 3 to 9, further comprising:c) optionally one or more disintegrants;d) optionally one or more surfactants;e) optionally one or more lubricants; and/orf) optionally one or more glidants.
- The pharmaceutical composition of claim 10, wherein the disintegrant is croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, starch, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate or any combination thereof.
- The pharmaceutical composition of any one of claims 9 to 11, wherein the surfactant is sodium lauryl sulfate, Tween 80, hydrogenated castor oil, polyethylene glycol-15-hydroxystearate, poloxamer or any combination thereof.
- The pharmaceutical composition of any one of claims 10 to 12, wherein the lubricant is stearic acid, magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, polyethylene glycol, carnauba wax, sodium lauryl sulfate, glyceryl palmitate stearate, palmitic acid, myristic acid, hydrogenated vegetable oil, fat or any combination thereof.
- The pharmaceutical composition of any one of claims 10 to 13, wherein the glidant is silicon dioxide, magnesium silicate, magnesium trisilicate, talc, micronized silica gel or any combination thereof.
- The pharmaceutical composition of any one of claims 3 to 14, optionally further comprising one or more binders, wherein the binder is hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, starch, pregelatinized starch, ethyl cellulose or any combination thereof.
- The pharmaceutical composition of any one of claims 1 to 15, optionally further comprising a coating agent, wherein the coating agent comprises a coating polymer; optionally, the coating agent further comprises one or more of the following substances: one or more plasticizers, one or more anti-adhesive agents, one or more glidants, one or more sunscreen agents and one or more colorants;wherein the coating polymer is hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, ethyl cellulose, methacrylic acid polymer, ethylene-vinyl acetate copolymer or any combination thereof.
- The pharmaceutical composition of any one of claims 1 to 16, wherein the compound having formula (I) , calculated as a percentage by weight, accounts for 5.0%-15%, 5.0%-14%, 7.0%-14.0%, 7.1%-13.5%, 7.0%-11.0%, or 7.1%-10.5%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 3 to 17, wherein the filler, calculated as a percentage by weight, accounts for 2%-95%, 10%-90%, 54%-90%, 55%-90%, 54%-87%, 70%-90%, 74%-87%, or 75%-86%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 10 to 18, wherein the disintegrant, calculated as a percentage by weight, accounts for 0-20%, 0-15%or 2%-15%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 9 to 19, wherein the surfactant, calculated as a percentage by weight, accounts for 0-15%, 0-10%, 0-8%, 0.5%-15%, 0.5%-8%, 0.5%-5%or 0-3%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 10 to 20, wherein the lubricant, calculated as a percentage by weight, accounts for 0-8%, 0-5%, 0.5%-8%, 0.5%-5%or 1.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 10 to 21, wherein the glidant, calculated as a percentage by weight, accounts for 0-20%, 0-10%, 0.5%-10%, 1%-10%or 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 15 to 22, wherein the binder, calculated as a percentage by weight, accounts for 0-20%, 0-10%or 0-3%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 3 to 23, comprising:a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,b) one or more fillers, wherein the filler is a combination of lactose and microcrystalline cellulose, or the filler is a combination of mannitol and microcrystalline cellulose, or the filler is a combination of mannitol and pregelatinized starch, or the filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch;c) optionally, one or more disintegrants, wherein the disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof;d) optionally, a surfactant, wherein the surfactant is sodium lauryl sulfate;e) optionally, a lubricant, wherein the lubricant is magnesium stearate; andf) optionally, a glidant, wherein the glidant is micronized silica gel.
- The pharmaceutical composition of any one of claims 3 to 24, optionally further comprising a binder, wherein the binder is hydroxypropyl methylcellulose.
- The pharmaceutical composition of claim 24 or 25, wherein the combination of lactose and microcrystalline cellulose, calculated as a percentage by weight, accounts for 10%-90%, 15%-87%, 15%-85%, 75%-86%or 78%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of lactose to microcrystalline cellulose is 1: 5-5: 1;or the combination of mannitol and microcrystalline cellulose, calculated as a percentage by weight, accounts for 10%-90%, 54%-87%, or 74%-77%of the weight of the pharmaceutical composition, wherein the weight ratio of microcrystalline cellulose to mannitol is 1: 5-5: 1;or the combination of mannitol and pregelatinized starch, calculated as a percentage by weight, accounts for 10%-90%or 79%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of mannitol to pregelatinized starch is 1: 5-5: 1;or the combination of lactose, microcrystalline cellulose and pregelatinized starch, calculated as a percentage by weight, accounts for 15%-90%, 75%-85%or 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%, 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-80%, 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%, 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 26, wherein the disintegrant, calculated as a percentage by weight, accounts for 0-15%, 1%-15%, 1%-5%or 2%-4%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 27, wherein the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5%-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 28, wherein the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-5%, 0.5%-3%or 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 29, wherein the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-10%, 0.5%-8%or 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 30, wherein the hydroxypropyl methylcellulose, calculated as a percentage by weight, accounts for 0-20%, 0-10%, 0.5%-5%or 1%-5%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 31, wherein the combination of lactose and microcrystalline cellulose, calculated as a percentage by weight, accounts for 15%-85%, 75%-86%or 78%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1;or the combination of mannitol and microcrystalline cellulose, calculated as a percentage by weight, accounts for 15%-85%, 54%-87%or 74%-77%of the weight of the pharmaceutical composition, wherein the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1;or the combination of mannitol and pregelatinized starch, calculated as a percentage by weight, accounts for 15%-85%or 79%-87%of the weight of the pharmaceutical composition, wherein the weight ratio of mannitol to pregelatinized starch is 1: 1.5;or the combination of lactose, microcrystalline cellulose and pregelatinized starch, calculated as a percentage by weight, accounts for 15%-85%, 75%-85%or 79%-80%of the weight of the pharmaceutical composition, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%, 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%, 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%, 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition; wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1.
- The pharmaceutical composition of any one of claims 24 to 32, wherein the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 33, wherein the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0-15%, 0.5%-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 34, wherein the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 35, wherein the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 36, wherein the hydroxypropyl cellulose, calculated as a percentage by weight, accounts for 1%-5%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 24 to 37, comprising:a) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof,b) one or more fillers, wherein the filler, calculated as a percentage by weight, accounts for 15%-85%, 50%-90%or 54%-87%of the weight of the pharmaceutical composition; wherein,the filler is a combination of lactose and microcrystalline cellulose, and the weight ratio of lactose to microcrystalline cellulose is 1: 3-5: 1; orthe filler is a combination of mannitol and microcrystalline cellulose, and the weight ratio of mannitol to microcrystalline cellulose is 1: 3-5: 1; orthe filler is a combination of mannitol and pregelatinized starch, and the weight ratio of mannitol to pregelatinized starch is 1: 1.5; orthe filler is a combination of lactose, microcrystalline cellulose and pregelatinized starch, wherein the lactose, calculated as a percentage by weight, accounts for 5%-80%, 50%-60%or 56%-57%of the weight of the pharmaceutical composition; the microcrystalline cellulose, calculated as a percentage by weight, accounts for 5%-60%, 10%-15%or 13%-14%of the weight of the pharmaceutical composition; the pregelatinized starch, calculated as a percentage by weight, accounts for 5%-60%, 5%-15%or 9.5%-10.5%of the weight of the pharmaceutical composition; and wherein the weight ratio of lactose to microcrystalline cellulose is 1: 2-5: 1.c) optionally, one or more disintegrants, wherein the disintegrant is croscarmellose sodium, sodium carboxymethyl starch, crospovidone or any combination thereof, and the disintegrant, calculated as a percentage by weight, accounts for 2%-4%of the weight of the pharmaceutical composition;d) optionally, a surfactant, wherein the surfactant is sodium lauryl sulfate, and the sodium lauryl sulfate, calculated as a percentage by weight, accounts for 0.5%-15%, 0.5%-8%or 0.5%-3%of the weight of the pharmaceutical composition;e) optionally, a lubricant, wherein the lubricant is magnesium stearate, and the magnesium stearate, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition; andf) optionally, a glidant, wherein the glidant is micronized silica gel, and the micronized silica gel, calculated as a percentage by weight, accounts for 0.5%-2%of the weight of the pharmaceutical composition.
- The pharmaceutical composition of claim 38, optionally further comprising a binder, wherein the binder is hydroxypropyl methylcellulose, and the hydroxypropyl methylcellulose, calculated as a percentage by weight, accounts for 1%to 5%of the total weight of the pharmaceutical composition.
- The pharmaceutical composition of any one of claims 1 to 39, wherein the particle size of the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof is D90 < 61 μm, D90 < 49 μm, D90 ≤ 48.6 μm, D90 ≤ 36 μm or D90 ≤ 28 μm.
- The pharmaceutical composition of any one of claims 1 to 40, wherein the pharmaceutical composition is a solid pharmaceutical preparation.
- The pharmaceutical composition of claim 41, wherein the solid pharmaceutical preparation is a powder, granule, tablet, capsule or pill.
- The pharmaceutical composition of any one of claims 1 to 42, which is administered once, twice, three times or four times a day.
- The pharmaceutical composition of any one of claims 1 to 43, further comprising other additional therapeutic agents, wherein the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an anti-hyperglycemic agent, an anti-obesity drug, an anti-hypertensive agent, an anti-platelet agent, an anti-atherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or any combination thereof.
- The pharmaceutical composition of claim 44, wherein the anti-diabetic agent other than an SGLT-2 inhibitor or anti-hyperglycemic agent is independently a biguanide drug, a sulfonylurea drug, a glucosidase inhibitor, a PPAR agonist, an αP2 inhibitor, a PPARα/γ dual agonist, a dipeptidyl peptidase IV inhibitor, a glinide drug, insulin, a glucagon-like peptide-1 inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor or any combination thereof;wherein the lipid-lowering agent is a MTP inhibitor, a HMGCoA reductase inhibitor, a squalene synthase inhibitor, a butyric acid-based lipid-lowering drug, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na (+) /bile acid cotransporter inhibitor, an upregulator of LDL receptor activity, niacin or a derivative thereof, a bile acid sequestrant or any combination thereof;wherein the lipid-lowering agent is pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, rosuvastatin or any combination thereof.
- Use of the pharmaceutical composition of any one of claims 1 to 45 in the manufacture of a medicament for inhibiting SGLT-2; or inhibiting SGLT-1; or increasing the level of high-density lipoprotein; or preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, syndrome X, atherosclerosis or hypertension.
- The pharmaceutical composition of any one of claims 1 to 45 for use in inhibiting SGLT-2; or inhibiting SGLT-1; or increasing the level of high-density lipoprotein; or preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases, wherein the disease is diabetes, diabetic complications, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, syndrome X, atherosclerosis or hypertension.
- A method of inhibiting SGLT-2; or inhibiting SGLT-1; or increasing the level of high-density lipoprotein in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 45.
- A method of preventing or treating the following diseases, alleviating the symptoms of the following diseases or delaying the development or onset of the following diseases in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 45, wherein the disease is diabetes, diabetic complications, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, syndrome X, atherosclerosis or hypertension.
- A method for preparing the pharmaceutical composition of any one of claims 3 to 42, comprising the following steps:1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants, binders and glidants, are mixed uniformly to obtain a premix;2) optionally, the lubricants and the premix are mixed uniformly to obtain a total mixed powder;3) the total mixed powder is filled into suitable hollow capsules.
- A method for preparing the pharmaceutical composition of any one of claims 3 to 42, comprising the following steps:1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants, binders and glidants, are mixed uniformly to obtain a premix;2) optionally, the lubricants and the premix are mixed uniformly to obtain a total mixed powder;3) the total mixed powder is pressed into tablets to obtain plain tablets;or1) the compound having formula (I) or a pharmaceutically acceptable salt, a solvate or a complex thereof and fillers, optionally, together with surfactants, disintegrants and binders, are subjected to wet granulation and drying to obtain dry particles;2) the lubricants, glidants and dry particles are mixed uniformly to obtain a total mixed powder;3) the total mixed powder is pressed into tablets to obtain plain tablets;
- The preparation method of claim 51, further comprising the step: coating the plain tablets to obtain coated tablets.
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WO2016173425A1 (en) * | 2015-04-30 | 2016-11-03 | Sunshine Lake Pharma Co., Ltd. | A glucopyranosyl derivative and preparation method and uses thereof |
CN106674294A (en) * | 2015-11-06 | 2017-05-17 | 广东东阳光药业有限公司 | Crystal form of glucopyranose derivative |
WO2017088839A1 (en) * | 2015-11-27 | 2017-06-01 | Sunshine Lake Pharma Co., Ltd. | A complex of a glucopyranosyl derivative and preparation method and use thereof |
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CN108239123A (en) * | 2016-12-27 | 2018-07-03 | 广东东阳光药业有限公司 | The eutectic of glucopyranosyl derivatives, preparation method and application |
WO2020143653A1 (en) * | 2019-01-08 | 2020-07-16 | 广东东阳光药业有限公司 | Preparation method for glucopyranosyl derivative and intermediate thereof |
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