A compound caffeine pharmaceutical composition, its preparation method and its application

Abstract

This invention relates to a compound caffeine pharmaceutical composition, comprising, by weight percentage, 10-40% caffeine hot-melt extrudate, 1-20% taurine, 0.1-2% vitamins, and a pharmaceutically acceptable carrier. The caffeine hot-melt extrudate is prepared by hot-melt extrusion of caffeine and the hot-melt extrusion carrier at a weight ratio of 1:1-8. The composition of this invention effectively masks the bitterness and astringency of caffeine, improves patient compliance, and significantly enhances the particle flowability, dispersion uniformity, and stability of the B vitamins, ensuring safe and effective medication.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a compound caffeine pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] The fast pace and high stress levels of modern life have led to a significant increase in the number of people experiencing fatigue globally each year. People experiencing fatigue often resort to products such as caffeine, taurine, and vitamins in an attempt to eliminate fatigue, maintain alertness, and improve work efficiency.

[0003] Caffeine, as a central nervous system stimulant, can increase the intracellular cyclic adenosine monophosphate (cAMP) content, stimulate the cerebral cortex, invigorate the spirit, and improve attention, self-confidence, work efficiency, and motivation; enhance alertness and reduce fatigue, improve vigilance and maintain sustained work capacity; shorten rapid selection reaction time, enhance recognition ability, and improve short-term memory, among other effects.

[0004] Taurine (2-aminoethanesulfonic acid, TAU) is a sulfur-containing amino acid and a conditionally essential amino acid with a wide range of physiological and pharmacological effects. It maintains homeostasis in the body, possesses antioxidant properties, protects biological membranes, scavenges free radicals, protects the heart, improves memory, and enhances visual signal transmission. It regulates carbohydrate and lipid metabolism, as well as the functions of the central nervous system, cardiovascular system, immune system, and endocrine system. It can promote the development of the nervous system in fetuses and infants, improve athletic ability and endurance, and alleviate exercise fatigue. It can also improve lipid peroxidation and calcium metabolism associated with exercise-induced fatigue. 2+ Problems such as homeostasis disorder, energy metabolism disorder, and damage to biological membranes.

[0005] B vitamins help maintain and regulate metabolism, improve athletic performance, and effectively prevent and alleviate free radical damage caused by excessive reactive oxygen species during high-intensity exercise. 12Cobalamin promotes the biosynthesis of DNA and proteins, enhances nerve nutrition and hematopoietic function, increases the oxygen-carrying capacity of red blood cells, promotes the development and maturation of red blood cells, maintains the normal state of the hematopoietic system, enhances the body's tolerance to hypoxia, improves exercise endurance, and prevents pernicious anemia. Vitamin B1 (thiosulfate) maintains the function of the nervous system, promotes metabolism and exercise capacity, and relieves fatigue. A deficiency in vitamin B1 affects glucose metabolism and leads to a decrease in hemoglobin production during sustained high-intensity aerobic exercise, thus affecting the body's tolerance to hypoxia, fatigue resistance, and exercise capacity. Vitamin B2 (riboflavin) is a component of two coenzymes (FAD, FMD) related to electron transfer and is closely related to enzymes involved in oxidation reactions in mitochondria, thus affecting energy consumption, muscle activity, and aerobic endurance. Calcium pantothenate is the calcium salt of vitamin B5 (pantothenic acid) and a component of coenzyme A. It participates in the metabolism and transformation of various amino acids, fats, and sugars in the human body, and is beneficial for maintaining the health of the heart, nervous system, digestive system, and skin. Vitamin B6 (pyridoxine) is related to the production of hemoglobin (Hb), myoglobin (Mb), and cytochromes. It promotes gluconeogenesis during exercise, prevents exercise-induced hypoglycemia, and improves the body's aerobic endurance.

[0006] Many commercially available caffeine products worldwide, made from caffeine, taurine, and B vitamins, suffer from the following drawbacks: first, the bitterness and astringency of caffeine affect swallowing and user compliance; second, the dosage of B vitamins is low, resulting in inconsistent quality and poor stability; and third, prolonged caffeine use can easily cause adverse reactions such as anxiety, irritability, insomnia, mood swings, and impaired fine motor skills. Therefore, there is an urgent need to develop caffeine products with better anti-fatigue effects and hypoxia tolerance, better quality and stability, greater safety and effectiveness, and ease of preparation to meet the growing demand from fatigued individuals, significantly improve their hypoxic state, and enhance their work efficiency. Summary of the Invention

[0007] The present invention aims to provide a compound caffeine pharmaceutical composition, comprising, by weight percentage, 10-40% caffeine hot-melt extrudate, 1-20% taurine, 0.1-2% vitamins and a pharmaceutically acceptable carrier. The caffeine hot-melt extrudate is prepared by hot-melt extrusion of caffeine and a hot-melt extrusion carrier at a weight ratio of 1:1-8. The hot-melt extrusion carrier is selected from any one or a combination of glyceryl monostearate, glyceryl distearate, mixed fatty acid glycerides, glyceryl behenate, stearic acid, magnesium stearate, calcium stearate, sodium stearate, and potassium stearate. The vitamins are selected from vitamin B1, vitamin B2, vitamin B3 (niacin), nicotinamide, calcium pantothenate, vitamin B6, vitamin B9 (folic acid), and vitamin B1. 12The pharmaceutically acceptable carrier is selected from any one or a combination of fillers, lubricants, flavorings, or combinations thereof.

[0008] In a preferred embodiment of the present invention, the composition contains 10-35% caffeine hot melt extruder, 2-15% taurine, and 0.2-1.5% vitamins, wherein the weight ratio of caffeine to hot melt extruder carrier in the caffeine hot melt extruder is 1:2-6.

[0009] In a preferred embodiment of the present invention, the composition contains 15-30% caffeine hot melt extruder, 4-13% taurine, and 0.5-1% vitamins, wherein the weight ratio of caffeine to hot melt extruder carrier in the caffeine hot melt extruder is 1:2.5-4.

[0010] In a preferred embodiment of the present invention, the weight ratio of vitamins to taurine in the composition is 1:10-20, preferably 1:12-18, and more preferably 1:13-15.

[0011] In a preferred embodiment of the present invention, the filler content in the composition is 35-75%, and the filler is selected from any one or a combination of mannitol, microcrystalline cellulose, guar gum, maltitol, sorbitol, xylitol, lactitol, erythritol, mannitol, and lactose.

[0012] In a preferred embodiment of the present invention, the filler content in the composition is 40-70%, preferably 45-65%.

[0013] In a preferred embodiment of the present invention, the content of lubricant in the composition is 0.1-10%, and the lubricant is selected from any one or a combination of fatty acids, stearic acid, talc, silicon dioxide, titanium dioxide, light silicic anhydride, micronized silica, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, glyceryl monostearate, glyceryl distearate, mixed fatty acid glyceryl ester, glyceryl behenate, sodium stearate, and potassium stearate.

[0014] In a preferred embodiment of the present invention, the content of lubricant in the composition is 0.5-8%, preferably 1-5%.

[0015] In a preferred embodiment of the present invention, the content of the flavoring agent in the composition is 1-10%, and the flavoring agent is selected from any one or a combination of citric acid, sucralose, aspartame, acesulfame potassium, steviol glycosides, pigments, lemon flavoring, peppermint flavoring, mixed berry flavoring, rose flavoring, and osmanthus flavoring.

[0016] In a preferred embodiment of the present invention, the flavoring agent content in the composition is 1.5-9.5%, preferably 2-9%.

[0017] In a preferred embodiment of the present invention, the composition contains 10-40% caffeine hot melt extrusion, 5-20% taurine, 0.05-1% vitamin B1, 0.05-1% calcium pantothenate, and vitamin B1. 12 0.001-0.1%, xylitol 30-70%, magnesium stearate 0.1-5%, citric acid 3-15%, sucralose 0.1-1% and flavoring 0.01-1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then by hot melt extrusion.

[0018] In a preferred embodiment of the present invention, the composition contains 15-35% caffeine hot melt extrusion, 8-15% taurine, 0.06-0.8% vitamin B1, 0.1-0.8% calcium pantothenate, and vitamin B2. 12 0.005-0.05%, xylitol 40-60%, magnesium stearate 0.5-3%, citric acid 5-12%, sucralose 0.2-0.8% and flavoring 0.05-0.5%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then hot melt extruding.

[0019] In a preferred embodiment of the present invention, the composition contains 20-30% caffeine hot melt extrudate, 10-13% taurine, 0.1-0.5% vitamin B1, 0.2-0.8% calcium pantothenate, and vitamin B2. 12 0.01-0.02%, xylitol 40-55%, magnesium stearate 1-2%, citric acid 5-10%, sucralose 0.3-0.6% and flavoring 0.06-0.1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then by hot melt extrusion.

[0020] In a preferred embodiment of the present invention, the composition contains 29.17% caffeine hot melt extrudate, 11.1% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B1. 12 0.01%, xylitol 49.01%-54.94%, sucralose 0.4%-0.5%, magnesium stearate 1%-3%, citric acid 2.5%-8.33% and flavoring 0.08%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding, and the flavoring is selected from either lemon flavoring or peppermint flavoring.

[0021] In a preferred embodiment of the present invention, the composition contains 18.753% caffeine hot melt extrudate, 7.14% taurine, 0.08% vitamin B1, 0.43% calcium pantothenate, and vitamin B1. 12The caffeine hot melt extruder contains 0.007% maltitol, 66.78% sucralose, 0.4% stearic acid, 1% citric acid, 5.36% lemon flavoring, and 0.05% caffeine. The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding.

[0022] In a preferred embodiment of the present invention, the composition contains 25% caffeine hot melt extrudate, 11.11% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B1. 12 0.01%, maltitol 59.11%, sucralose 0.4%, citric acid 2.5%, peppermint flavor 0.08% and behenicol glyceryl 1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding.

[0023] In a preferred embodiment of the present invention, the pharmaceutical composition is anhydrous oral granules.

[0024] In a preferred embodiment of the present invention, the water content of the anhydrous oral granules is ≤3%, preferably ≤2.5%.

[0025] Another object of the present invention is to provide a method for preparing a compound caffeine pharmaceutical composition, wherein, by weight percentage, the composition contains 10-40% caffeine hot-melt extrudate, 1-20% taurine, 0.1-2% vitamins and a pharmaceutically acceptable carrier, wherein the caffeine hot-melt extrudate is prepared by hot-melt extrusion of caffeine and hot-melt extrusion carrier in a weight ratio of 1:1-8, wherein the hot-melt extrusion carrier is selected from any one or a combination of glyceryl monostearate, glyceryl distearate, mixed fatty acid glycerides, glyceryl behenate, stearic acid, magnesium stearate, calcium stearate, sodium stearate, and potassium stearate, and the vitamins are selected from vitamin B1, vitamin B2, vitamin B3 (niacin), nicotinamide, calcium pantothenate, vitamin B6, vitamin B9 (folic acid), and vitamin B1. 12 The pharmaceutically acceptable carrier is selected from any one or a combination of fillers, lubricants, flavoring agents, or combinations thereof, and the method includes the following steps:

[0026] (1) Weigh the required amount of caffeine and hot melt extrusion carrier, mix them evenly, and then perform hot melt extrusion treatment. After crushing the obtained hot melt extrusion particles, pass them through a 30-50 mesh sieve to obtain caffeine hot melt extrusion.

[0027] (2) Weigh out the required amount of flavoring agent, mix it evenly with the caffeine hot melt extrusion, and then mix it with the required amount of vitamin B. 12 After the solution is uniformly mixed, it is wet-granulated to obtain a soft material.

[0028] (3) After passing the prepared soft material through a 10-20 mesh sieve, it is dried in a fluidized bed to obtain dried granules;

[0029] (4) Mix the dried granules with other components evenly to obtain the final product.

[0030] In a preferred embodiment of the present invention, caffeine is pulverized and passed through a 40-80 mesh sieve, xylitol is pulverized and passed through a 30-50 mesh sieve, and citric acid is pulverized and passed through a 40-50 mesh sieve.

[0031] In the preferred embodiment of the present invention, the mixing conditions in step (1) are: stirring speed 200-800 rpm, chopping speed 500-1000 rpm, mixing for 5-30 min, preferably stirring speed 400-500 rpm, chopping speed 600-800 rpm, mixing for 10-20 min.

[0032] In the preferred embodiment of the present invention, the hot melt extrusion conditions are: 50-200℃, screw speed 50-200rpm, preferably 60-150℃, screw speed 100-150rpm.

[0033] In the preferred embodiment of the present invention, the wet granulation conditions are: stirring speed 200-800 rpm, chopping speed 500-1000 rpm, mixing for 5-30 min, preferably stirring speed 400-500 rpm, chopping speed 600-800 rpm, mixing for 10-20 min.

[0034] In a preferred embodiment of the present invention, the fluidized bed drying conditions are 50-100℃ and an air volume of 10-50 m³ / h. 3 Drying time: 5-30 min, preferably 60-80℃, air volume: 15-30 m³ / h. 3 / h, dry for 10-20 minutes.

[0035] In a preferred embodiment of the present invention, the moisture content of the dried particles is ≤3%, preferably ≤2.5%.

[0036] In the preferred embodiment of the present invention, the mixing conditions in step (4) are: mixing at 10-50 rpm for 5-30 min, preferably at 15-20 rpm for 10-20 min.

[0037] In a preferred embodiment of the present invention, the composition contains 10-35% caffeine hot melt extruder, 2-15% taurine, and 0.2-1.5% vitamins, wherein the weight ratio of caffeine to hot melt extruder carrier in the caffeine hot melt extruder is 1:2-6.

[0038] In a preferred embodiment of the present invention, the composition contains 15-30% caffeine hot melt extruder, 4-13% taurine, and 0.5-1% vitamins, wherein the weight ratio of caffeine to hot melt extruder carrier in the caffeine hot melt extruder is 1:2.5-4.

[0039] In a preferred embodiment of the present invention, the weight ratio of vitamins to taurine in the composition is 1:10-20, preferably 1:12-18, and more preferably 1:13-15.

[0040] In a preferred embodiment of the present invention, the filler content in the composition is 35-75%, and the filler is selected from any one or a combination of mannitol, microcrystalline cellulose, guar gum, maltitol, sorbitol, xylitol, lactitol, erythritol, mannitol, and lactose.

[0041] In a preferred embodiment of the present invention, the filler content in the composition is 40-70%, preferably 45-65%.

[0042] In a preferred embodiment of the present invention, the content of lubricant in the composition is 0.1-10%, and the lubricant is selected from any one or a combination of fatty acids, stearic acid, talc, silicon dioxide, titanium dioxide, light silicic anhydride, micronized silica, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, glyceryl monostearate, glyceryl distearate, mixed fatty acid glyceryl ester, glyceryl behenate, sodium stearate, and potassium stearate.

[0043] In a preferred embodiment of the present invention, the content of lubricant in the composition is 0.5-8%, preferably 1-5%.

[0044] In a preferred embodiment of the present invention, the content of the flavoring agent in the composition is 1-10%, and the flavoring agent is selected from any one or a combination of citric acid, sucralose, aspartame, acesulfame potassium, steviol glycosides, pigments, lemon flavoring, peppermint flavoring, mixed berry flavoring, rose flavoring, and osmanthus flavoring.

[0045] In a preferred embodiment of the present invention, the flavoring agent content in the composition is 1.5-9.5%, preferably 2-9%.

[0046] In a preferred embodiment of the present invention, the composition contains 10-40% caffeine hot melt extrusion, 5-20% taurine, 0.05-1% vitamin B1, 0.05-1% calcium pantothenate, and vitamin B1. 12 0.001-0.1%, xylitol 30-70%, magnesium stearate 0.1-5%, citric acid 3-15%, sucralose 0.1-1% and flavoring 0.01-1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then by hot melt extrusion.

[0047] In a preferred embodiment of the present invention, the composition contains 15-35% caffeine hot melt extrusion, 8-15% taurine, 0.06-0.8% vitamin B1, 0.1-0.8% calcium pantothenate, and vitamin B2. 12 0.005-0.05%, xylitol 40-60%, magnesium stearate 0.5-3%, citric acid 5-12%, sucralose 0.2-0.8% and flavoring 0.05-0.5%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then hot melt extruding.

[0048] In a preferred embodiment of the present invention, the composition contains 20-30% caffeine hot melt extrudate, 10-13% taurine, 0.1-0.5% vitamin B1, 0.2-0.8% calcium pantothenate, and vitamin B2. 12 0.01-0.02%, xylitol 40-55%, magnesium stearate 1-2%, citric acid 5-10%, sucralose 0.3-0.6% and flavoring 0.06-0.1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then by hot melt extrusion.

[0049] In a preferred embodiment of the present invention, the composition contains 29.17% caffeine hot melt extrudate, 11.1% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B1. 12 0.01%, xylitol 49.01%-54.94%, sucralose 0.4%-0.5%, magnesium stearate 1%-3%, citric acid 2.5%-8.33% and flavoring 0.08%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding, and the flavoring is selected from either lemon flavoring or peppermint flavoring.

[0050] In a preferred embodiment of the present invention, the composition contains 18.753% caffeine hot melt extrudate, 7.14% taurine, 0.08% vitamin B1, 0.43% calcium pantothenate, and vitamin B1. 12 The caffeine hot melt extruder contains 0.007% maltitol, 66.78% sucralose, 0.4% stearic acid, 1% citric acid, 5.36% lemon flavoring, and 0.05% caffeine. The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding.

[0051] In a preferred embodiment of the present invention, the composition contains 25% caffeine hot melt extrudate, 11.11% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B1. 120.01%, maltitol 59.11%, sucralose 0.4%, citric acid 2.5%, peppermint flavor 0.08% and behenicol glyceryl 1%, wherein the caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding.

[0052] In a preferred embodiment of the present invention, the pharmaceutical composition is anhydrous oral granules.

[0053] In a preferred embodiment of the present invention, the water content of the anhydrous oral granules is ≤3%, preferably ≤2.5%.

[0054] Another object of the present invention is to provide the use of the compound caffeine pharmaceutical composition of the present invention in the preparation of a medicament for relieving fatigue symptoms.

[0055] In a preferred embodiment of the present invention, the fatigue symptoms are selected from any one or a combination of lethargy, poor concentration, fatigue and weakness, decreased recognition ability, and decreased memory.

[0056] Another object of the present invention is to provide the use of the compound caffeine composition of the present invention in the preparation of energy supplements.

[0057] Unless otherwise stated, the present invention uses the following methods to detect particle repose angle, bulk density and tap density.

[0058] 1. Angle of repose determination: The angle of repose of the particles was determined using a powder property tester. The test was performed in three parallel tests, and the average value was calculated.

[0059] 2. Determination of bulk density and tapped density: Weigh an appropriate amount of the particles to be tested and place them in a 25ml graduated cylinder of the powder property tester. Record the initial volume and particle weight. Then, place the graduated cylinder on the powder property tester and tap it. Set the amplitude to 3mm, the tapping frequency to 250Hz, and the number of tapping cycles to 300. Measure the tapped density. Then, calculate the density according to the Karl index = (tapped density - bulk density) / tapped density * 100% and the Hausner ratio = tapped density / bulk density. Perform three parallel tests and take the average value of the three tests. Characterize the flowability of the particles through the Karl index and the Hausner ratio.

[0060] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0061] Compared with the prior art, the present invention has the following beneficial technical effects:

[0062] 1. This invention scientifically combines caffeine with taurine, B vitamins, and other anti-fatigue components in a specific ratio to synergistically enhance the energizing and refreshing effects of caffeine, producing multiple anti-fatigue benefits, including replenishing energy, improving physical performance, enhancing mental alertness, reducing reaction time, and alleviating physical fatigue. 2. The use of hot-melt caffeine extrusion effectively masks the bitterness, astringency, and other unpleasant odors of caffeine, improving user compliance. 3. The formulation into anhydrous granules eliminates the need for water, solving the problems of inconvenience and difficulty swallowing, making it suitable for various populations (including children and the elderly), and easy to carry, further improving user compliance. 4. It significantly improves the granule flowability of the composition, effectively addressing the uniformity and stability of B vitamin content, significantly improving the quality uniformity, stability, and bioavailability of the composition. 5. It specifically supplements vitamin B. 12 It enhances nerve nutrition and hematopoietic function, increases the oxygen-carrying capacity of red blood cells, enhances the body's tolerance to hypoxia, helps improve exercise endurance and prevent the occurrence of pernicious anemia, significantly improves the composition's tolerance to hypoxia, efficiently replenishes physical energy, and has the advantages of excellent tolerance to hypoxia, anti-mental fatigue and anti-physical fatigue.

[0063] 2. The preparation method of the present invention has the advantages of simple operation, high yield, shortened production cycle, economic convenience, better cost, and suitability for industrial production. Attached Figure Description

[0064] Figure 1 Sensory evaluation of the compound caffeine compositions prepared in Examples 1-4 and Comparative Examples 1-4. Detailed Implementation

[0065] The present invention will be described below with reference to the embodiments. However, the present invention is not limited to the embodiments.

[0066] Example 1: Preparation of a compound caffeine composition

[0067] The composition of the compound caffeine composition is as follows:

[0068]

[0069]

[0070] A method for preparing a compound caffeine composition includes the following steps:

[0071] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; xylitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0072] (2) Weigh 75g of caffeine and 187.5g of magnesium stearate and mix them for 10 minutes at a stirring speed of 400rpm and a chopping speed of 800rpm. After uniform mixing, feed the mixture into a hot melt extruder. The hot melt extrusion temperature is 130-150℃ (the module temperature is set as follows), and the screw speed is 100rpm. Extrude the mixture into strips, crush it, and pass it through a 40-mesh sieve to obtain caffeine hot melt extrudate.

[0073] Module mold opening 8 7 6 5 4 3 2 Temperature ℃ 140 147 147 145 145 140 135 130

[0074] (3) Place the obtained caffeine hot melt extrudate, citric acid, and sucralose in a wet granulator. Under the conditions of stirring speed of 400 rpm and chopping speed of 800 rpm, spray in the required amount of vitamin B. 12 The solution was wet-granulated for 10 minutes to obtain a soft material.

[0075] (4) After the soft material is passed through an 18-mesh sieve, it is placed in a fluidized bed for drying. The air inlet temperature is set to 60°C and the air inlet volume is adjusted to allow the material to be blown up. The material is dried until the moisture content of the particles is ≤3%. According to the method described in this invention, the angle of repose of the dried particles is 38°, the Karl index is 16%, the H ratio is 1.20, and the fluidity is good.

[0076] (5) After the dried granules are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0077] Example 2: Preparation of Compound Caffeine Pharmaceutical Composition

[0078] The composition of the compound caffeine drug composition is as follows:

[0079]

[0080] The preparation method of the compound caffeine pharmaceutical composition includes the following steps:

[0081] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; xylitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0082] (2) Weigh 75g of caffeine and 187.5g of magnesium stearate and mix them for 10 minutes at a stirring speed of 400rpm and a chopping speed of 800rpm. After uniform mixing, feed the mixture into a hot melt extruder. The hot melt extrusion temperature is 120-150℃ (the module temperature is set as follows), and the screw speed is 150rpm. Extrude the mixture into strips, crush it, and pass it through a 40-mesh sieve to obtain caffeine hot melt extrusion.

[0083] Module mold opening 8 7 6 5 4 3 2 Temperature ℃ 110 117 117 115 115 110 120 115

[0084] (3) Place the obtained caffeine hot melt extrudate with the required amount of citric acid and sucralose in a wet granulator, and spray in vitamin B while stirring at 400 rpm and chopping at 800 rpm. 12 The solution was wet-granulated for 10 minutes to obtain a soft material.

[0085] (4) Pass the soft material through an 18-mesh sieve, and then place the resulting granules in a fluidized bed for drying. Set the inlet air temperature to 60°C and adjust the inlet air volume to allow the material to be blown up. Dry until the moisture content of the granules is ≤3%. According to the method described in this invention, the dried granules have a repose angle of 40°, a Karl Fischer index of 19%, an H ratio of 1.23, and good flowability.

[0086] (5) After the dried granules are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0087] Example 3: Preparation of Compound Caffeine Pharmaceutical Composition

[0088] The composition of the compound caffeine drug composition is as follows:

[0089]

[0090]

[0091] The preparation method of the compound caffeine pharmaceutical composition includes the following steps:

[0092] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; maltitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0093] (2) Weigh 75g of caffeine and 187.5g of magnesium stearate, mix them for 10 minutes at a stirring speed of 400rpm and a chopping speed of 800rpm, and then feed them into a hot melt extruder. The hot melt extrusion temperature is 60-80℃ (the module temperature is set as follows), the screw speed is 120rpm, and the material is extruded into strips. After crushing, the material is passed through a 40-mesh sieve to obtain caffeine hot melt extrudate.

[0094] Module mold opening 8 7 6 5 4 3 2 Temperature ℃ 70 75 75 73 73 73 72 72

[0095] (3) Place the obtained caffeine hot melt extrudate with the required amount of citric acid and sucralose in a wet granulator, and spray in vitamin B while stirring at 400 rpm and chopping at 800 rpm. 12 The solution was wet-granulated for 10 minutes to obtain a soft material.

[0096] (4) Pass the soft material through an 18-mesh sieve, and then place the resulting granules in a fluidized bed for drying. Set the inlet air temperature to 60°C and adjust the inlet air volume to allow the material to be blown up. Dry until the moisture content of the granules is ≤3%. According to the method described in this invention, the dried granules have a repose angle of 39°, a Karl Fischer index of 18%, an H ratio of 1.22, and good flowability.

[0097] (5) After the dried granules are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0098] Example 4: Preparation of Compound Caffeine Pharmaceutical Composition

[0099] The composition of the compound caffeine drug composition is as follows:

[0100]

[0101] The preparation method of the compound caffeine composition includes the following steps:

[0102] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; maltitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0103] (2) Weigh 75g of caffeine and 150g of behenicol glycerides, mix them for 10 minutes at a stirring speed of 400rpm and a chopping speed of 800rpm, and then feed them into a hot melt extruder. The hot melt extrusion temperature is 60-80℃ (the module temperature is set as follows), the screw speed is 120rpm, and the material is extruded into strips. After crushing, the material is passed through a 40-mesh sieve to obtain caffeine hot melt extrusion.

[0104] Module mold opening 8 7 6 5 4 3 2 Temperature ℃ 75 80 80 77 77 77 75 75

[0105] (3) Place the obtained caffeine hot melt extrudate with the required amount of citric acid and sucralose in a wet granulator, and spray in vitamin B while stirring at 400 rpm and chopping at 800 rpm. 12 The solution was wet-granulated for 10 minutes to obtain a soft material.

[0106] (4) Pass the soft material through an 18-mesh sieve, and then place the resulting granules in a fluidized bed for drying. Set the inlet air temperature to 60°C and adjust the inlet air volume to allow the material to be blown up. Dry until the moisture content of the granules is ≤3%. According to the method described in this invention, the dried granules have a repose angle of 37°, a Karl Fischer index of 17%, an H ratio of 1.21, and good flowability.

[0107] (5) After the dried granules are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0108] Comparative Example 1: Preparation of Caffeine Powder

[0109] Weigh out 75g of caffeine, grind it, and pass it through an 80-mesh sieve.

[0110] Comparative Example 2: Preparation of Compound Caffeine Composition

[0111] The composition of the compound caffeine composition is as follows:

[0112]

[0113] The preparation method of the compound caffeine pharmaceutical composition includes the following steps:

[0114] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; maltitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0115] (2) Mix the components at a stirring speed of 400 rpm and a chopping speed of 800 rpm for 10 min to obtain the final product.

[0116] Preparation of compound caffeine composition in Comparative Example 3

[0117] The composition of the compound caffeine composition is as follows:

[0118]

[0119] The preparation of the compound caffeine composition includes the following steps:

[0120] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; maltitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0121] (2) Caffeine, citric acid and xylitol were mixed for 10 minutes at a stirring speed of 400 rpm and a chopping speed of 800 rpm to obtain a mixture;

[0122] (3) Add an appropriate amount of purified water to the mixture to make a soft material that can be kneaded into a ball. Pass the soft material through an 18-mesh sieve, and then place the resulting granules in a fluidized bed to dry. Set the air inlet temperature to 60°C and adjust the air inlet volume to allow the material to be blown up. Dry until the moisture content of the granules is ≤3%.

[0123] (4) After the dried granules are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0124] Comparative Example 4: Preparation of Compound Caffeine Composition

[0125] The composition of the compound caffeine composition is as follows:

[0126]

[0127] The preparation of the compound caffeine composition includes the following steps:

[0128] (1) Pre-treatment: Caffeine is ground and passed through an 80-mesh sieve; maltitol is ground and passed through a 30-mesh sieve; citric acid is ground and passed through a 40-mesh sieve.

[0129] (2) Add caffeine, citric acid, and xylitol to the fluidized bed reactor, adjust the airflow to ensure good material fluidization, and adjust the peristaltic pump speed of the fluidized bed to 3.0 rpm and the atomization pressure to 1.6 kg / m³. 2 Add an appropriate amount of 30% xylitol aqueous solution and spray granulation from the top until the material in the pot is granulated. Dry until the moisture content of the granules is less than 3%.

[0130] (3) After the dried particles are sized by passing them through an 18-mesh sieve, they are mixed with the remaining components at 25 rpm for 10 min to obtain the final product.

[0131] Experimental Example 1: Study on Antibody Fatigue of the Compound Caffeine Composition of the Present Invention

[0132] One hundred and twenty healthy male Ba lb / c mice, weighing (20±2) g, were purchased from the Vital River Laboratory Animal Center. They were housed in the same room but separated by cages for one week for acclimatization, with the ambient temperature controlled at 25±2℃ and a light exposure of 12 h. During the experiment, the experimental animals had free access to water and food.

[0133] The experimental mice were randomly divided into 5 groups: a resting control group, an exercise control group, and low-dose, medium-dose, and high-dose groups of the compound caffeine composition (Example 1), with 24 mice in each group. The resting control group and the exercise control group were administered physiological saline by gavage at a dose of 10 mL / kg, while the low-dose, medium-dose, and high-dose groups of the compound caffeine were administered compound caffeine aqueous solution by gavage at doses of 8 mL / kg, 10 mL / kg, and 12 mL / kg, respectively. The administration was once daily for 7 consecutive days.

[0134] 1. Exhaustion swimming time of experimental mice

[0135] Thirty minutes after the last gavage, six mice from each group were randomly selected for a weighted swimming test. Lead weights equal to 5% of the mice's body weight were tied to their tails, and the mice were placed in a water tank approximately 30 cm deep at a temperature of 25℃ ± 0.5℃. The time from the start of swimming until death was recorded as the exhaustion swimming time. The results are shown in Table 1 (x0 ± s, n = 6).

[0136] Table 1

[0137]

[0138] Note: Compared with the exercise control group. * P < 0.05 ** P < 0.01.

[0139] Compared with the exercise control group, the swimming time of mice in the treatment group was significantly prolonged (P<0.05), indicating that the compound caffeine composition of the present invention has excellent anti-fatigue activity.

[0140] 2. Determination of serum urea nitrogen

[0141] Thirty minutes after the last gavage, six mice from each group were randomly selected and placed in water at 25℃±0.5℃ for 90 minutes to swim without load. After resting for 60 minutes, 0.1 mL of blood was collected from the orbital cavity. After the blood clotted, it was centrifuged, and the serum was collected and tested according to the Nanjing Jiancheng reagent kit. The results are shown in Table 2 (x0±s, n=6).

[0142] Table 2

[0143]

[0144] Note: Compared with the exercise control group. * P < 0.05 ** P < 0.01; compared with the quiet control group, # P < 0.05 ## P < 0.01.

[0145] Compared with the quiet control group, the serum urea nitrogen in all groups of mice showed an increasing trend, but was lower than that in the exercise control group, and the difference was significant (P<0.05). The medium-dose group and the high-dose group showed good ability to clear serum urea nitrogen metabolites in exercised mice.

[0146] 3. Blood lactate measurement

[0147] Thirty minutes after the last gavage, six mice from each group were randomly selected and swam in water at 25℃±0.5℃ for 60 minutes with a load of 2% of their body weight. After resting for 15 minutes, 0.1 mL of blood was collected from the orbital cavity, mixed with 0.6 mL of protein precipitant, centrifuged at 4000 rpm for 10 minutes, and the supernatant was collected and analyzed according to the Nanjing Jiancheng reagent kit. The results are shown in Table 3 (x0±s, n=6).

[0148] Table 3

[0149]

[0150] Note: Compared with the exercise control group. * P < 0.05 ** P < 0.01; compared with the quiet control group, # P < 0.05 ## P < 0.01.

[0151] Compared with the quiet control group, the blood lactate content of mice increased significantly after swimming for 60 minutes. Compared with the exercise control group, the blood lactate content of the medium-dose group and the high-dose group was significantly reduced (P<0.01). The compound caffeine composition of the present invention can effectively metabolize lactate and relieve physical fatigue.

[0152] 4. Liver glycogen assay

[0153] Thirty minutes after the last gavage, six mice were randomly selected from each group. They were then immersed in water at 25℃±0.5℃ for 90 minutes without any negative pressure, followed by immediate euthanasia by cervical dislocation. The liver was removed, rinsed with physiological saline, and blotted dry with filter paper. Approximately 50 mg of liver tissue was weighed and added to 150 μL of 30% NaOH solution. The mixture was incubated in a boiling water bath for 20 minutes, then 0.8 mL of water was added and mixed to prepare a 5% reaction solution. 0.5 mL of the reaction solution was added to 0.5 mL of water, mixed, and 2 mL of anthrone reagent was added. The mixture was incubated in a boiling water bath for 5 minutes and measured colorimetrically at 620 nm according to the Nanjing Jiancheng reagent kit requirements. The results are shown in Table 4 (x0±s, n=6).

[0154] Table 4

[0155]

[0156] Note: Compared with the exercise control group. * P < 0.05 ** P < 0.01; compared with the quiet control group, # P < 0.05 ## P < 0.01.

[0157] In the exercise control group, the liver glycogen content of mice decreased rapidly compared with the resting group. The medium-dose and high-dose groups showed significant differences compared with the exercise control group (P < 0.05), and were closer to normal levels. The compound caffeine composition of this invention can increase liver glycogen content and significantly alleviate fatigue.

[0158] Example 2: Sensory evaluation experiment of the compound caffeine composition of the present invention

[0159] Five subjects were recruited to taste the compound caffeine drug compositions prepared in Examples 1-4 and Comparative Examples 1-4. The granules were poured directly into the mouth without the need for water. Subjects rinsed their mouths before and between taking either composition to avoid any flavor interference from other foods or the compositions.

[0160] Bitterness rating: 1 point indicates the strongest bitterness, 2 points indicates a relatively strong bitterness, 3 points indicates a moderate bitterness, 4 points indicates a mild bitterness, and 5 points indicates almost no bitterness. The average score from 5 participants was used. See [link to results]. Figure 1 Examples 1-4 do not have a bitter taste.

[0161] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A compound caffeine pharmaceutical composition, comprising, by weight percentage, 10-40% caffeine hot-melt extrudate, 1-20% taurine, 0.1-2% vitamins, and a pharmaceutically acceptable carrier, wherein, The caffeine hot-melt extrudate is composed of caffeine and a hot-melt extrusion carrier at a weight ratio of 1:2-4, and is obtained by hot-melt extrusion. The hot-melt extrusion carrier is selected from any one or a combination of glyceryl behenate, stearic acid, magnesium stearate, and calcium stearate. The vitamin is selected from vitamin B. 12 The combination with other vitamins, wherein the other vitamins are selected from any one or a combination of vitamin B1, vitamin B2, vitamin B3 (niacin), nicotinamide, calcium pantothenate, vitamin B6, vitamin B9 (folic acid), and the pharmaceutically acceptable carrier is selected from any one or a combination of fillers, lubricants, flavoring agents.

2. The composition of claim 1, wherein the composition contains 15-30% caffeine hot melt extrudate, 4-13% taurine, and 0.5-1% vitamin, wherein, The weight ratio of caffeine to the hot melt extruder in the caffeine hot melt extrusion is 1:2.5-4.

3. The composition according to claim 1, wherein the weight ratio of vitamin to taurine in the composition is 1:10-20.

4. The composition according to claim 3, wherein the weight ratio of vitamin to taurine in the composition is 1:12-18.

5. The composition according to claim 4, wherein the weight ratio of vitamin to taurine in the composition is 1:13-15.

6. The composition of claim 1, wherein the filler content in the composition is 35-75%, and the filler is selected from any one or a combination of mannitol, microcrystalline cellulose, guar gum, maltitol, sorbitol, xylitol, lactitol, erythritol, mannitol, and lactose.

7. The composition of claim 6, wherein the filler content in the composition is 40-70%.

8. The composition of claim 7, wherein the filler content in the composition is 45-65%.

9. The composition of claim 1, wherein the content of lubricant in the composition is 0.1-10%, and the lubricant is selected from any one or a combination of stearic acid, talc, silicon dioxide, titanium dioxide, light silica anhydride, micronized silica, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, glyceryl monostearate, glyceryl distearate, mixed fatty acid glyceryl ester, glyceryl behenate, sodium stearate, and potassium stearate.

10. The composition of claim 9, wherein the content of lubricant in the composition is 0.5-8%.

11. The composition of claim 10, wherein the content of lubricant in the composition is 1-5%.

12. The composition of claim 1, wherein the composition contains 10-40% caffeine hot melt extrudate, 5-20% taurine, 0.05-1% vitamin B1, 0.05-1% calcium pantothenate, and vitamin B2. 12 0.001-0.1%, xylitol 30-70%, magnesium stearate 0.1-5%, citric acid 3-15%, sucralose 0.1-1%, and flavoring 0.01-1%, of which, The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then performing hot melt extrusion.

13. The composition of claim 12, wherein the composition contains 15-35% caffeine hot melt extrudate, 8-15% taurine, 0.06-0.8% vitamin B1, 0.1-0.8% calcium pantothenate, and vitamin B2. 12 0.005-0.05%, xylitol 40-60%, magnesium stearate 0.5-3%, citric acid 5-12%, sucralose 0.2-0.8%, and flavoring 0.05-0.5%, of which, The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then performing hot melt extrusion.

14. The composition of claim 13, wherein the composition contains 20-30% caffeine hot melt extrudate, 10-13% taurine, 0.1-0.5% vitamin B1, 0.2-0.8% calcium pantothenate, and vitamin B2. 12 0.01-0.02%, xylitol 40-55%, magnesium stearate 1-2%, citric acid 5-10%, sucralose 0.3-0.6%, and flavoring 0.06-0.1%, of which, The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a weight ratio of 1:2.5 and then performing hot melt extrusion.

15. The composition of claim 14, wherein the composition contains 29.17% caffeine hot melt extrudate, 11.1% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B1. 12 0.01%, xylitol 49.01%-54.94%, sucralose 0.4%-0.5%, magnesium stearate 1%-3%, citric acid 2.5%-8.33%, and flavoring 0.08%, of which... The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then hot melt extruding. The flavoring is selected from either lemon flavoring or peppermint flavoring.

16. The composition of claim 1, wherein the composition contains 18.753% caffeine hot melt extrudate, 7.14% taurine, 0.08% vitamin B1, 0.43% calcium pantothenate, and vitamin B2. 12 0.007%, maltitol 66.78%, sucralose 0.4%, stearic acid 1%, citric acid 5.36%, and lemon flavoring 0.05%, of which... The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then performing hot melt extrusion.

17. The composition of claim 1, wherein the composition contains 25% caffeine hot melt extrudate, 11.11% taurine, 0.12% vitamin B1, 0.67% calcium pantothenate, and vitamin B2. 12 0.01%, maltitol 59.11%, sucralose 0.4%, citric acid 2.5%, peppermint flavor 0.08%, and behenicol glyceride 1%, of which, The caffeine hot melt extruder is prepared by mixing caffeine and magnesium stearate in a mass ratio of 1:2.5 and then performing hot melt extrusion.

18. The composition according to any one of claims 1-17, wherein the pharmaceutical composition is anhydrous oral granules.

19. The composition of claim 18, wherein the water content of the anhydrous oral granules is ≤3%.

20. The composition of claim 19, wherein the water content of the anhydrous oral granules is ≤2.5%.

21. A method for preparing a compound caffeine pharmaceutical composition according to any one of claims 1-20, the method comprising the following steps: (1) Weigh the required amount of caffeine and hot melt extrusion carrier, mix them evenly, and then perform hot melt extrusion. After crushing the obtained hot melt extrusion particles, pass them through a 30-50 mesh sieve to obtain caffeine hot melt extrusion. (2) Weigh out the required amount of flavoring agent, mix it evenly with the caffeine hot melt extrusion, and then mix it with the required amount of vitamin B. 12 After the solution is uniformly mixed, it is wet-granulated to obtain a soft material. (3) After passing the prepared soft material through a 10-20 mesh sieve, it is dried in a fluidized bed to obtain dried granules; (4) Mix the dried granules with the other components evenly to obtain the final product.

22. The method as described in claim 21, wherein the mixing conditions in step (1) are: stirring speed 200-800 rpm, chopping speed 500-1000 rpm, and mixing for 5-30 min.

23. The method as described in claim 22, wherein the mixing conditions in step (1) are: stirring speed 400-500 rpm, chopping speed 600-800 rpm, and mixing for 10-20 min.

24. The method as described in claim 21, wherein the hot melt extrusion conditions are: 50-200℃ and screw speed 50-200rpm.

25. The method of claim 24, wherein the hot melt extrusion conditions are: 60-150°C and screw speed 100-150 rpm.

26. The method of claim 21, wherein the wet granulation conditions are: stirring speed 200-800 rpm, chopping speed 500-1000 rpm, and mixing for 5-30 min.

27. The method of claim 26, wherein the wet granulation conditions are: stirring speed 400-500 rpm, chopping speed 600-800 rpm, and mixing for 10-20 min.

28. The method as described in claim 21, wherein the fluidized bed drying conditions are 50-100℃ and an air volume of 10-50 m³ / h. 3 / h, dry for 5-30min.

29. The method as described in claim 28, wherein the fluidized bed drying conditions are 60-80°C and an air volume of 15-30 m³ / h. 3 / h, dry for 10-20min.

30. The method according to any one of claims 21-29, wherein the moisture content of the dried particles is ≤3%.

31. The method of claim 30, wherein the moisture content of the dried particles is ≤2.5%.

32. The method according to any one of claims 21-29, wherein the mixing conditions in step (4) are: mixing at 10-50 rpm for 5-30 min.

33. The method as described in claim 32, wherein the mixing conditions in step (4) are: mixing at 15-20 rpm for 10-20 min.

34. The use of the compound caffeine pharmaceutical composition according to any one of claims 1-20 or the compound caffeine pharmaceutical composition prepared by the method according to any one of claims 21-33 in the preparation of a medicament for relieving fatigue symptoms.

35. The application as described in claim 34, wherein the fatigue symptoms are selected from any one or a combination of lethargy, inattention, fatigue, decreased cognitive ability, and decreased memory.

36. The use of the compound caffeine pharmaceutical composition according to any one of claims 1-20 or the compound caffeine pharmaceutical composition prepared by the method according to any one of claims 21-33 in the preparation of energy supplements.

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