Composition containing quick-release delivery composition and slow-release delivery composition as well as preparation method and application thereof

Abstract

The invention discloses a composition containing an immediate release delivery composition and a sustained release delivery composition as well as a preparation method and application of the composition. The quick-release delivery composition contains alpha-ketoglutaric acid or pharmaceutically acceptable salts thereof, can quickly release alpha-ketoglutaric acid or pharmaceutically acceptable salts thereof in a gastrointestinal tract pH environment, and has a good application prospect in the large health industry, such as health care products, food or drugs. The medicine composition is simple in preparation method, good in smoothness and suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a combination comprising an immediate-release delivery composition and a sustained-release delivery composition, its preparation method, and its uses. Background Technology

[0002] α-Ketoglutarate is an important intermediate in muscle metabolism. During muscle activity, both the tricarboxylic acid cycle and glutamate deamination produce large amounts of α-ketoglutarate. Previous studies have shown that α-ketoglutarate plays a crucial regulatory role in protein synthesis, skeletal muscle development and metabolism, and calcium homeostasis. α-Ketoglutarate can regulate physiological processes such as muscle and bone development, cell metabolism, immune inflammation, and stem cell development through complex signaling pathways. These advances are of great significance for the application of α-ketoglutarate.

[0003] To ensure rapid onset of action after ingestion, it is necessary to develop an oral formulation of α-ketoglutarate that can quickly reach an effective concentration in vivo. Preferably, to simultaneously achieve both rapid onset and long-lasting efficacy, the oral formulation further needs to meet the dual requirements of immediate and sustained release, which poses a challenge to the development of oral formulations of α-ketoglutarate. Summary of the Invention

[0004] The purpose of this invention is to provide an immediate-release delivery composition that can substantially completely release α-ketoglutarate or its pharmaceutically acceptable salt within 0.5 hours.

[0005] In a first aspect, the present invention provides an immediate-release delivery composition comprising α-ketoglutarate or a pharmaceutically acceptable salt thereof, wherein the immediate-release delivery composition can substantially completely release α-ketoglutarate or a pharmaceutically acceptable salt thereof within 0.5 hours.

[0006] In some embodiments, the immediate-release delivery composition can substantially completely release α-ketoglutaric acid or its pharmaceutically acceptable salt within 0.5 hours in release media at pH 1.2, pH 4.5, and pH 6.8.

[0007] In some embodiments, "basic release complete" means that more than 70% of α-ketoglutarate or a pharmaceutically acceptable salt thereof is released from the immediate-release delivery composition.

[0008] In some embodiments, "basic release complete" means that more than 80% of α-ketoglutarate or its pharmaceutically acceptable salt is released from the immediate-release delivery composition.

[0009] In some embodiments, "basic release complete" means that more than 90% of α-ketoglutarate or its pharmaceutically acceptable salt is released from the immediate-release delivery composition.

[0010] In some embodiments, the α-ketoglutarate or a pharmaceutically acceptable salt thereof is selected from one or more of α-ketoglutarate, sodium α-ketoglutarate, potassium α-ketoglutarate, ammonium α-ketoglutarate, calcium α-ketoglutarate, and magnesium α-ketoglutarate, preferably one or more of α-ketoglutarate, sodium α-ketoglutarate, potassium α-ketoglutarate, and calcium α-ketoglutarate, more preferably α-ketoglutarate or calcium α-ketoglutarate, and most preferably calcium α-ketoglutarate.

[0011] In some embodiments, the α-ketoglutarate or a pharmaceutically acceptable salt thereof constitutes 20%-80% of the total weight of the immediate-release delivery composition, preferably 30%-70%, more preferably 40%-60%, and even more preferably 45%-55%.

[0012] In some embodiments, the immediate-release delivery composition further comprises one or more of a filler, disintegrant, binder, lubricant, and sweetener.

[0013] In some embodiments, the immediate-release delivery composition further comprises one or more of a filler, a disintegrant, a binder, and a lubricant.

[0014] In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, starch, sucrose, mannitol, and sorbitol, preferably one or more of lactose, microcrystalline cellulose, and mannitol, and more preferably microcrystalline cellulose.

[0015] In some embodiments, the filler accounts for 2%-60% of the total weight of the immediate-release delivery composition, preferably 5%-50%, more preferably 10%-40%, further preferably 20%-30%, and most preferably 23%.

[0016] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the filler in the immediate-release delivery composition is 100:20-80, preferably 100:30-60, more preferably 100:40-60, and even more preferably 100:40-50.

[0017] In some embodiments, the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose, and croscarmellose sodium, preferably sodium carboxymethyl starch or croscarmellose sodium, and more preferably sodium carboxymethyl starch.

[0018] In some embodiments, the disintegrant accounts for 1%-30% of the total weight of the immediate-release delivery composition, preferably 1%-20%, more preferably 1%-10%, further preferably 1%-5%, and most preferably 3%.

[0019] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the disintegrant in the immediate-release delivery composition is 100:1-20, preferably 100:2-15, and more preferably 100:5-10.

[0020] In some embodiments, the adhesive is selected from one or more of starch paste, povidone, gelatin, and polyethylene glycol, preferably starch paste or povidone, and more preferably povidone.

[0021] In some embodiments, the adhesive comprises 1%-30% of the total weight of the immediate-release delivery composition, preferably 1%-20%, more preferably 1%-10%, further preferably 1%-5%, and most preferably 3%.

[0022] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the binder in the immediate-release delivery composition is 100:1-20, preferably 100:2-15, and more preferably 100:5-10.

[0023] In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, talc, and silicon dioxide, preferably one or more of magnesium stearate and silicon dioxide, and more preferably magnesium stearate.

[0024] In some embodiments, the lubricant accounts for 0.5%-10% of the total weight of the immediate-release delivery composition, preferably 1%-10%, more preferably 1%-5%, further preferably 1%-3%, and most preferably 2%.

[0025] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the lubricant in the immediate-release delivery composition is 100:1-10, preferably 100:2-10, and more preferably 100:2-5.

[0026] In some embodiments, the sweetener is selected from one or more of aspartame, acesulfame potassium, sucralose, and steviol glycoside, preferably aspartame or sucralose, and more preferably sucralose.

[0027] In some embodiments, the sweetener comprises 0.5%-20% of the total weight of the immediate-release delivery composition, preferably 1%-10%, more preferably 2%-8%.

[0028] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the sweetener in the immediate-release delivery composition is 100:0.2-10, preferably 100:0.5-6, and more preferably 100:1-4.

[0029] In some embodiments, the immediate-release delivery composition further comprises one or more of the following vitamins: vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin F, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, biotin, folic acid, mixed tocopherols, orotic acid, and tocotrienols.

[0030] In some implementations, the vitamin is a single vitamin.

[0031] In some implementations, the vitamin is a multivitamin.

[0032] In some embodiments, the vitamin accounts for 1%-40% of the total weight of the immediate-release delivery composition, preferably 10%-30%, more preferably 15%-25%.

[0033] In some embodiments, the immediate-release delivery composition comprises 20%-80% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 2%-60% of filler, 1%-30% of disintegrant, 1%-30% of binder, and 0.5%-10% of lubricant.

[0034] In some embodiments, the immediate-release delivery composition comprises 30%-70% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 5%-50% of filler, 1%-20% of disintegrant, 1%-20% of binder and 1%-10% of lubricant.

[0035] In some embodiments, the immediate-release delivery composition comprises 40%-60% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 10%-40% of filler, 1%-10% of disintegrant, 1%-10% of binder, and 1%-5% of lubricant.

[0036] In some embodiments, the immediate-release delivery composition comprises 45%-55% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 20%-30% of filler, 1%-5% of disintegrant, 1%-5% of binder, and 1%-3% of lubricant.

[0037] In some embodiments, the immediate-release delivery composition comprises 50% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 23% filler, 3% disintegrant, 3% binder, and 2% lubricant.

[0038] In some embodiments, the immediate-release delivery composition comprises 50% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 23% filler, 3% disintegrant, 3% binder, 2% lubricant, and 19% vitamin.

[0039] In a second aspect, the present invention provides a combination comprising the immediate-release delivery composition described in the first aspect and a sustained-release delivery composition. The delivery composition rapidly releases α-ketoglutarate or a pharmaceutically acceptable salt thereof to achieve rapid onset of action, while also possessing a sustained-release function to continuously release α-ketoglutarate or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the combination can substantially completely release α-ketoglutarate or its pharmaceutically acceptable salt in the immediate-release delivery composition within 0.5 hours, and can sustain the release of α-ketoglutarate or its pharmaceutically acceptable salt in the sustained-release delivery composition for 10-12 hours.

[0041] In some embodiments, α-ketoglutarate or a pharmaceutically acceptable salt thereof in the combination releases 20%-40% at 0.5 hours, 60%-80% at 6 hours, and more than 80% at 12 hours.

[0042] In some embodiments, the mass ratio of the immediate-release delivery composition to the sustained-release delivery composition in the combination is 9:1-5:5, preferably 8:2-6:4, and more preferably 8:2-7:3.

[0043] In some embodiments, the combination is a kit for combined administration, wherein the immediate-release delivery composition and the sustained-release delivery composition may be administered together, administered independently at the same time, or administered separately at time intervals.

[0044] In some implementations, the combination is a fixed combination in the form of dose units, such as a bilayer tablet.

[0045] In some embodiments, the sustained-release delivery composition comprises α-ketoglutarate or a pharmaceutically acceptable salt thereof, and the mass ratio of α-ketoglutarate or a pharmaceutically acceptable salt thereof in the immediate-release delivery composition and the sustained-release delivery composition is 9:1-5:5, preferably 8:2-6:4, and more preferably 8:2-7:3.

[0046] In some embodiments, the α-ketoglutarate or a pharmaceutically acceptable salt thereof in the sustained-release delivery composition is selected from one or more of α-ketoglutarate, sodium α-ketoglutarate, potassium α-ketoglutarate, and ammonium α-ketoglutarate, preferably one or more of α-ketoglutarate, sodium α-ketoglutarate, and potassium α-ketoglutarate, and more preferably α-ketoglutarate.

[0047] In some embodiments, α-ketoglutarate or a pharmaceutically acceptable salt thereof constitutes 20%-80% of the total weight of the sustained-release delivery composition, preferably 30%-70%, more preferably 40%-60%, and even more preferably 45%-55%.

[0048] In some embodiments, the sustained-release delivery composition further comprises one or more of a sustained-release material, a filler, a binder, a lubricant, a bioadhesive, and a sweetener.

[0049] In some embodiments, the sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, chitosan, sodium alginate, and carnauba wax, preferably one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, ethylcellulose, and methylcellulose, more preferably one or more of hydroxypropyl methylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose, and even more preferably hydroxypropyl methylcellulose.

[0050] In some embodiments, the sustained-release material accounts for 10%-60% of the total weight of the sustained-release delivery composition, preferably 20%-50%, more preferably 30%-45%, further preferably 35%-40%, and most preferably 37%.

[0051] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the sustained-release material in the sustained-release delivery composition is 100:50-90, preferably 100:60-90, more preferably 100:65-85, and even more preferably 100:70-80.

[0052] In some embodiments, the filler in the sustained-release delivery composition is selected from one or more of lactose, microcrystalline cellulose, starch, sucrose, mannitol, sorbitol, and erythritol, preferably one or more of lactose, microcrystalline cellulose, starch, sucrose, mannitol, sorbitol, and erythritol, more preferably one or more of lactose, microcrystalline cellulose, and mannitol, and even more preferably microcrystalline cellulose.

[0053] In some embodiments, the filler in the sustained-release delivery composition accounts for 1%-30% of the total weight of the sustained-release delivery composition, preferably 1%-20%, more preferably 1%-10%, further preferably 1%-5%, and most preferably 5%.

[0054] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the filler in the sustained-release delivery composition is 100:5-95, preferably 100:5-80, more preferably 100:5-60, further preferably 100:5-40, even more preferably 100:5-20, and even more preferably 100:5-15.

[0055] In some embodiments, the binder in the sustained-release delivery composition is selected from one or more of starch paste, povidone, gelatin, and polyethylene glycol, preferably starch paste or povidone, more preferably povidone.

[0056] In some embodiments, the binder in the sustained-release delivery composition accounts for 1%-30% of the total weight of the sustained-release delivery composition, preferably 2%-20%, more preferably 2%-10%.

[0057] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the binder in the sustained-release delivery composition is 100:1-20, preferably 100:2-15, and more preferably 100:5-10.

[0058] In some embodiments, the lubricant in the sustained-release delivery composition is selected from one or more of stearic acid, magnesium stearate, talc, and silicon dioxide, preferably one or more of magnesium stearate and silicon dioxide, and more preferably magnesium stearate and silicon dioxide.

[0059] In some embodiments, the lubricant in the sustained-release delivery composition accounts for 1%-10% of the total weight of the sustained-release delivery composition, preferably 2%-8%, more preferably 4%-8%, and even more preferably 6%.

[0060] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the lubricant in the sustained-release delivery composition is 100:2-20, preferably 100:5-15, and more preferably 100:10-15.

[0061] In some embodiments, the bioadhesive in the sustained-release delivery composition is selected from one or more of polyvinyl alcohol, carbomer, carrageenan, gelatin, and deacetylated chitosan, preferably carbomer.

[0062] In some embodiments, the bioadhesive in the sustained-release delivery composition accounts for 1%-30% of the total weight of the sustained-release delivery composition, preferably 1%-20%, more preferably 1%-10%, further preferably 1%-4%, and most preferably 2%.

[0063] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the bioadhesive in the sustained-release delivery composition is 100:1-40, preferably 100:2-20, and more preferably 100:2-10.

[0064] In some embodiments, the sweetener in the sustained-release delivery composition is selected from one or more of aspartame, acesulfame potassium, sucralose, and steviol glycoside, preferably aspartame or sucralose, and more preferably sucralose.

[0065] In some embodiments, the sweetener in the sustained-release delivery composition accounts for 0.5%-20% of the total weight of the sustained-release delivery composition, preferably 1%-10%, more preferably 1%-5%, and even more preferably 2%.

[0066] In some embodiments, the mass ratio of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof to the sweetener in the sustained-release delivery composition is 100:0.2-10, preferably 100:0.5-6, and more preferably 100:1-4.

[0067] In some embodiments, the sustained-release delivery composition comprises 20%-80% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof and 10%-60% by weight of sustained-release material.

[0068] In some embodiments, the sustained-release delivery composition comprises 30%-70% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof and 20%-50% by weight of sustained-release material.

[0069] In some embodiments, the sustained-release delivery composition comprises 40%-60% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof and 30%-45% by weight of sustained-release material.

[0070] In some embodiments, the sustained-release delivery composition comprises 45%-55% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof and 35%-40% by weight of sustained-release material.

[0071] In some embodiments, the sustained-release delivery composition comprises 50% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof and 37% by weight of sustained-release material.

[0072] In some embodiments, the sustained-release delivery composition comprises 20%-80% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 10%-60% of sustained-release material, 1%-30% of filler, 1%-10% of lubricant, and 1%-30% of bioadhesive.

[0073] In some embodiments, the sustained-release delivery composition comprises 30%-70% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 20%-50% sustained-release material, 1%-20% filler, 1%-8% lubricant, and 1%-20% bioadhesive.

[0074] In some embodiments, the sustained-release delivery composition comprises 40%-60% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 30%-45% of sustained-release material, 1%-10% of filler, 2%-8% of lubricant, and 1%-10% of bioadhesive.

[0075] In some embodiments, the sustained-release delivery composition comprises 45%-55% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 35%-40% of sustained-release material, 1%-5% of filler, 4%-8% of lubricant, and 1%-4% of bioadhesive.

[0076] In some embodiments, the sustained-release delivery composition comprises 50% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 37% sustained-release material, 5% filler, 6% lubricant, and 2% bioadhesive.

[0077] In some embodiments, the sustained-release delivery composition comprises 50% by weight of α-ketoglutaric acid or a pharmaceutically acceptable salt thereof, 37% sustained-release material, 2% filler, 6% lubricant, and 2% bioadhesive.

[0078] Thirdly, the present invention provides a method for preparing the immediate-release delivery composition described in the first aspect, comprising the following steps:

[0079] 1) Granulation was performed using α-ketoglutaric acid or its pharmaceutically acceptable salt via wet granulation;

[0080] 2) Tableting.

[0081] In some embodiments, the α-ketoglutaric acid or its pharmaceutically acceptable salt is pulverized through a sieve, preferably a 0.25 mm sieve.

[0082] In some embodiments, the α-ketoglutarate or its pharmaceutically acceptable salt is wet-granulated after being uniformly mixed with vitamins.

[0083] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof is mixed uniformly with the filler and then wet-granulated.

[0084] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof is wet-granulated after being uniformly mixed with a disintegrant.

[0085] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof is wet-granulated after being uniformly mixed with a binder.

[0086] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof is wet-granulated after being uniformly mixed with fillers, disintegrants, binders and optional sweeteners.

[0087] In some embodiments, a wetting agent is added during the wet granulation process, preferably water.

[0088] In some embodiments, the wet granulation process further includes granulation and drying steps, controlling the particle moisture content to be below 5%, preferably below 4%, and more preferably below 3%.

[0089] In some embodiments, the particles obtained by wet granulation are mixed uniformly with the disintegrant.

[0090] In some embodiments, the particles obtained by the wet granulation are mixed uniformly with a lubricant and optionally a disintegrant.

[0091] In some embodiments, the granules obtained by the wet granulation are mixed uniformly with a lubricant and optionally a disintegrant and / or a sweetener.

[0092] Fourthly, the present invention provides a method for preparing the combination described in the second aspect above, comprising the following steps:

[0093] 1) The α-ketoglutaric acid or its pharmaceutically acceptable salt in the immediate-release and sustained-release delivery compositions are wet-granulated separately;

[0094] 2) Tableting.

[0095] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is pulverized through a sieve, preferably a 0.25 mm sieve.

[0096] In some embodiments, the α-ketoglutarate or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is wet-granulated after being uniformly mixed with vitamins.

[0097] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is wet-granulated after being uniformly mixed with the filler.

[0098] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is wet-granulated after being uniformly mixed with a disintegrant.

[0099] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is wet-granulated after being uniformly mixed with a binder.

[0100] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the immediate-release delivery composition is wet-granulated after being uniformly mixed with fillers, disintegrants, binders and optional sweeteners.

[0101] In some embodiments, the immediate-release delivery composition is wet-granulated with a wetting agent, preferably water.

[0102] In some embodiments, the wet granulation of the immediate-release delivery composition further includes granulation and drying steps, controlling the particle moisture content to be less than 5%, preferably less than 4%, and more preferably less than 3%.

[0103] In some embodiments, the immediate-release delivery composition is uniformly mixed with a disintegrant in the particles obtained by wet granulation.

[0104] In some embodiments, the immediate-release delivery composition is uniformly mixed with a lubricant and optionally a disintegrant in the particles obtained by wet granulation.

[0105] In some embodiments, the immediate-release delivery composition is uniformly mixed with a lubricant and optionally a disintegrant and / or a sweetener in the particles obtained by wet granulation.

[0106] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the sustained-release delivery composition is pulverized through a sieve, preferably a 0.5 mm sieve.

[0107] In some embodiments, the α-ketoglutaric acid or a pharmaceutically acceptable salt thereof of the sustained-release delivery composition is wet-granulated after being uniformly mixed with the filler.

[0108] In some embodiments, the sustained-release delivery composition is wet-granulated with a wetting agent, preferably water.

[0109] In some embodiments, the wet granulation of the sustained-release delivery composition further includes granulation and drying steps, controlling the particle moisture content to be less than 5%, preferably less than 4%, and more preferably less than 3%.

[0110] In some embodiments, the sustained-release delivery composition is uniformly mixed with the sustained-release material in the particles obtained by wet granulation.

[0111] In some embodiments, the sustained-release delivery composition is uniformly mixed with a lubricant in particles obtained by wet granulation.

[0112] In some embodiments, the sustained-release delivery composition is uniformly mixed with the bioadhesive in particles obtained by wet granulation.

[0113] In some embodiments, the sustained-release delivery composition is uniformly mixed with a lubricant, a bioadhesive, and optionally a binder and / or sweetener in the particles obtained by wet granulation.

[0114] In some implementations, the double-layer tableting is performed using a double-layer tableting machine.

[0115] All technical features disclosed in this invention, or all steps in all methods or processes disclosed, may be combined in any way, except for mutually exclusive technical features and / or steps.

[0116] Fifthly, the present invention provides the use of the immediate-release delivery composition described in the first aspect or the combination described in the second aspect in the preparation of health products, foods, or pharmaceuticals. Preferably, the present invention provides the use of the immediate-release delivery composition described in the first aspect or the combination described in the second aspect in the preparation of health products, foods, or pharmaceuticals with anti-aging, antioxidant, anti-inflammatory, cellular energy metabolism regulation, mitochondrial function enhancement, immune regulation, and tissue repair and regeneration promotion effects.

[0117] The beneficial effects of this invention are as follows:

[0118] 1. The immediate-release delivery composition of the present invention can substantially completely release α-ketoglutaric acid or its pharmaceutically acceptable salt within 0.5 hours, thereby achieving rapid onset of action.

[0119] 2. The combination of the present invention can rapidly release α-ketoglutarate or its pharmaceutically acceptable salt, while also having a sustained-release function. α-ketoglutarate or its pharmaceutically acceptable salt can be continuously released for 10-12 hours, which has the dual advantages of rapid onset of action and sustained efficacy.

[0120] 3. The combination of the present invention has excellent chemical stability, can be stored for a long time and maintain the content of α-ketoglutarate in the delivery composition essentially unchanged.

[0121] 4. The preparation method of the present invention is simple, smooth, and suitable for large-scale production. The immediate-release delivery composition prepared by the method of the present invention can release α-ketoglutarate or its pharmaceutically acceptable salts almost completely within 0.5 hours under the pH environment of the gastrointestinal tract. The combination prepared by the method of the present invention has both immediate-release and sustained-release functions, and has the dual advantages of rapid onset and sustained efficacy. Detailed Implementation

[0122] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0123] As used herein, the term "immediate release" refers to the rapid release of the active ingredient in a composition in a release medium or after administration. In some embodiments, the active ingredient in an immediate-release delivery composition is substantially completely released within 0.5 hours in a release medium. In some embodiments, the active ingredient in an immediate-release delivery composition is substantially completely released within 0.5 hours in release media at pH 1.2, pH 4.5, and pH 6.8.

[0124] As used herein, the term "sustained release" refers to the slow and sustained release of the active ingredient in a composition in a release medium or after administration. For example, in a release medium, the active ingredient is released at a rate of 60%-80% at 6 hours and at a rate of more than 80% at 12 hours; preferably, the active ingredient is released at a rate of 40%-60% at 2 hours, at a rate of 60%-80% at 6 hours, and at a rate of more than 80% at 12 hours.

[0125] As used herein, the term "release medium" refers to a solution that mimics the pH of the gastrointestinal tract, such as a pH 1.2 hydrochloric acid solution, a pH 4.5 acetate buffer, or a pH 6.8 phosphate buffer, which can be prepared according to the methods described in the pharmacopoeia.

[0126] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of an active ingredient consisting of a cationic form of the active ingredient and a suitable anion, or a salt form of an anionic form of the active ingredient and a suitable cation, which is generally safe, non-toxic, and acceptable for biological, pharmaceutical, or health food use. "α-Ketoglutarate or a pharmaceutically acceptable salt thereof" includes, but is not limited to, α-ketoglutarate, sodium α-ketoglutarate (e.g., monosodium α-ketoglutarate, disodium α-ketoglutarate), potassium α-ketoglutarate (e.g., monopotassium α-ketoglutarate, dipotassium α-ketoglutarate), ammonium α-ketoglutarate, calcium α-ketoglutarate, magnesium α-ketoglutarate, zinc α-ketoglutarate, meglumine α-ketoglutarate, ethanolamine α-ketoglutarate, aminobutanetriol α-ketoglutarate, lysine α-ketoglutarate, ornithine α-ketoglutarate, or arginine α-ketoglutarate. Typically, the active ingredient has higher solubility and dissolution rate in gastric and intestinal fluids when it is salted. α-Ketoglutarate or its pharmaceutically acceptable salts can be provided in anhydrous, hemihydrate, monohydrate, or dihydrate form.

[0127] As used herein, the term "sustained-release material" refers to a substance that can prevent or delay the release of an active ingredient from a formulation in a release medium or in the gastrointestinal fluid of a human or animal. For example, some hydrophilic polymers contain a large number of hydrophilic groups, such as hydroxyl groups, which swell upon contact with water to form a gel barrier. Through diffusion and dissolution, they synergistically control the slow release of the active ingredient in a water-containing physiological environment, thereby achieving the purpose of slow release in the digestive tract, prolonging absorption time, and reducing adverse irritation.

[0128] As used herein, the term "bioadhesive" refers to a biocompatible substance that adheres to the surface of the gastrointestinal wall to increase the retention time of a formulation in the gastrointestinal tract. It can be a natural or artificially manufactured polymer, such as a polysaccharide-based adhesive, polyethylene glycol, polyacrylic acid derivatives (e.g., carbomer), polyamine, or urethane variants.

[0129] As used herein, the term "combination" refers to a set of pill kits or a fixed combination of dosage units for combined administration.

[0130] As used herein, the term “about” means within ±20%, ±10%, ±5%, or ±2% of the stated value.

[0131] Unless otherwise specified, percentages in this application refer to weight percentages.

[0132] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without a specified manufacturer are all commercially available conventional products. In the following embodiments, α-ketoglutarate arginine salt is L-arginine-α-ketoglutarate (2:1).

[0133] Example 1

[0134] Immediate-release delivery composition: Calcium α-ketoglutarate was pulverized using a 0.25mm sieve, and then mixed with compound vitamins, microcrystalline cellulose, sodium carboxymethyl starch, povidone, and water. The mixture was wet-granulated in a wet mixing granulator, sized, and dried to control the moisture content to below 3.0%. Magnesium stearate was added and mixed for 5-10 minutes.

[0135] Sustained-release delivery composition: α-ketoglutaric acid was pulverized using a 0.5 mm sieve, mixed evenly with microcrystalline cellulose, and wet granulated with purified water. The granules were then sized, dried, and the moisture content was controlled to be below 3.0%. The granules were then mixed with carbomer, hydroxypropyl methylcellulose K100M, magnesium stearate, and silica for 5-10 minutes.

[0136] The bilayer tablet is compressed using a bilayer tablet press. First, the sustained-release delivery composition is compressed into a sustained-release layer, and then the immediate-release delivery composition and the sustained-release layer are compressed into a bilayer tablet. The weight of the bilayer tablet is controlled to be 1000 mg ± 3%.

[0137] The content of each component in each double-layer tablet is shown in Table 1.

[0138] Table 1. Composition of bilayer sheets

[0139]

[0140] Example 2

[0141] Following the method of Example 1, the calcium α-ketoglutarate in the immediate-release delivery composition was replaced with an equal amount of α-ketoglutarate, while the remaining components and contents were the same as in Example 1, and a bilayer tablet was prepared.

[0142] Comparative Example 1

[0143] Following the method of Example 1, the calcium α-ketoglutarate in the immediate-release delivery composition was replaced with an equal amount of α-ketoglutarate arginine salt, while the remaining components and contents were the same as in Example 1, and a bilayer tablet was prepared.

[0144] Comparative Example 2

[0145] Bilayer sheets were prepared according to the method in Example 1, and the content of each component in each bilayer sheet is shown in Table 2.

[0146] Table 2 Composition of bilayer sheets

[0147]

[0148] Test Example 1: In vitro release rate detection of the bilayer tablets of the present invention

[0149] According to the release rate detection method in the Chinese Pharmacopoeia, the release rate of the bilayer tablets in the examples and comparative examples was determined over 12 hours using the paddle method. The release medium volume was 900 mL, the temperature was 37℃±0.5℃, and the stirring speed was 50 rpm. The release media were pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, respectively. The released samples were detected by high performance liquid chromatography, and the release rate was calculated. The release results are shown in Tables 3-5.

[0150] Table 3. Release rate of bilayer tablets in pH 1.2 medium

[0151]

[0152] Table 4. Release rate of bilayer tablets in pH 4.5 medium

[0153]

[0154] " / " indicates that it was not detected.

[0155] Table 5. Release rate of bilayer tablets in pH 6.8 medium

[0156]

[0157] In release media at pH 1.2, pH 4.5, and pH 6.8, the saturated solubility of α-ketoglutarate arginine was greater than 150 mg / mL, significantly higher than that of calcium α-ketoglutarate. Surprisingly, however, the release results of Comparative Example 1 showed that the α-ketoglutarate arginine in the immediate-release layer could not be completely released within 0.5 hours in these release media. However, the calcium α-ketoglutarate in the immediate-release layer of Example 1 and the α-ketoglutarate in the immediate-release layer of Example 2 could release 20%-40% of the active ingredient in the bilayer tablets within 0.5 hours, indicating that the active ingredient in the immediate-release layer was essentially completely released, achieving rapid onset of action.

[0158] The release results of the bilayer tablets in Examples 1 and 2 showed similar release rates in release media at pH 1.2, pH 4.5, and pH 6.8. The release rate of the active ingredient was 20%-40% at 0.5 hours, 40%-60% at 2 hours, 60%-80% at 6 hours, and above 80% at 12 hours, indicating that the bilayer tablets of Examples 1 and 2 can rapidly take effect and stably and continuously release the active ingredient in the gastrointestinal environment. Comparative Examples 1 and 2 could not effectively release the active ingredient within the specified time and failed to meet the ideal release rate limit requirements.

[0159] Test Example 2: Stability Testing of the Bilayer Sheet of the Present Invention

[0160] The bilayer tablets of the present invention were stored at 40°C and 75% relative humidity and at 30°C and 65% relative humidity, respectively. After a certain period of time, the content of α-ketoglutaric acid in the bilayer tablets was detected by high performance liquid chromatography. The results are shown in Table 6.

[0161] Table 6. Content of α-ketoglutarate in bilayer tablets

[0162]

[0163] The bilayer tablets of Example 1 exhibit excellent chemical stability, with the α-ketoglutaric acid content remaining essentially unchanged during storage. Compared to the compositions of the comparative examples, selecting the active ingredients of the example compositions, particularly the active ingredients of the immediate-release layer, to prepare the bilayer tablets is beneficial for long-term storage.

[0164] The embodiments described above are some, but not all, embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. An immediate-release delivery composition comprising α-ketoglutarate or a pharmaceutically acceptable salt thereof, wherein the immediate-release delivery composition can substantially completely release α-ketoglutarate or a pharmaceutically acceptable salt thereof within 0.5 hours.

2. The immediate-release delivery composition according to claim 1, characterized in that, The α-ketoglutaric acid or its pharmaceutically acceptable salt is selected from one or more of α-ketoglutaric acid, sodium α-ketoglutarate, potassium α-ketoglutarate, ammonium α-ketoglutarate, calcium α-ketoglutarate, and magnesium α-ketoglutarate, preferably one or more of α-ketoglutaric acid, sodium α-ketoglutarate, potassium α-ketoglutarate, and calcium α-ketoglutarate, more preferably α-ketoglutaric acid or calcium α-ketoglutarate, and most preferably calcium α-ketoglutarate.

3. The immediate-release delivery composition according to claim 1 or 2, characterized in that, The α-ketoglutaric acid or a pharmaceutically acceptable salt thereof accounts for 20%-80% of the total weight of the immediate-release delivery composition, preferably 30%-70%, more preferably 40%-60%, and even more preferably 45%-55%.

4. The immediate-release delivery composition according to any one of claims 1-3, characterized in that, The immediate-release delivery composition further comprises one or more of a filler, a disintegrant, a binder, and a lubricant.

5. A combination comprising the immediate-release delivery composition according to any one of claims 1-4, and the sustained-release delivery composition.

6. The combination according to claim 5, characterized in that, The sustained-release delivery composition comprises α-ketoglutarate or a pharmaceutically acceptable salt thereof, and the mass ratio of α-ketoglutarate or a pharmaceutically acceptable salt thereof in the immediate-release delivery composition and the sustained-release delivery composition is 9:1-5:5, preferably 8:2-6:4, and more preferably 8:2-7:

3.

7. The combination according to claim 5 or 6, characterized in that, The sustained-release delivery composition contains α-ketoglutarate or a pharmaceutically acceptable salt thereof selected from one or more of α-ketoglutarate, sodium α-ketoglutarate, potassium α-ketoglutarate, and ammonium α-ketoglutarate, preferably one or more of α-ketoglutarate, sodium α-ketoglutarate, and potassium α-ketoglutarate, and more preferably α-ketoglutarate.

8. A method for preparing the immediate-release delivery composition according to any one of claims 1-4, comprising the following steps: 1) Granulation was performed using α-ketoglutaric acid or its pharmaceutically acceptable salt via wet granulation; 2) Tableting.

9. A method for preparing the combination according to any one of claims 5-7, comprising the following steps: 1) The α-ketoglutaric acid or its pharmaceutically acceptable salt in the immediate-release and sustained-release delivery compositions are wet-granulated separately; 2) Tableting.

10. Use of the immediate-release delivery composition according to any one of claims 1-4 or the combination according to any one of claims 5-7 in the preparation of health products, food or pharmaceuticals.

Images