Levocarnitine chewable tablet as well as preparation method and application thereof

Abstract

The invention provides levocarnitine chewable tablets as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The levocarnitine chewable tablet disclosed by the invention is prepared from levocarnitine, modified hydroxypropyl methyl cellulose, microcrystalline cellulose PH102, sodium carboxymethyl starch, quaternized chitosan, sodium caprate, sulfobutyl ether-beta-cyclodextrin, mannitol, sorbitol, sodium stearyl fumarate and superfine silica powder. The modified hydroxypropyl methyl cellulose is prepared from hydroxypropyl methyl cellulose through citric acid crosslinking and 1, 2-propylene glycol carbonate reaction in sequence, initial release and later slow release of the levocarnitine can be controlled, and long-acting release of the levocarnitine is achieved. The levocarnitine chewable tablet can realize stable release of levocarnitine and maintain stable blood concentration, has palatability and high bioavailability, is especially suitable for patients with dysphagia, and has important clinical value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a levocarnitine chewable tablet and a preparation method and application thereof. BACKGROUND

[0002] Levocarnitine, also known as L-carnitine, is a naturally occurring amino acid derivative that plays an important role in human energy metabolism. Its main function is to promote the entry of long-chain fatty acids into mitochondria for beta-oxidation, thereby providing energy for the body. Levocarnitine is widely used in the treatment of cardiomyopathy, muscle weakness, metabolic disorders and other diseases caused by carnitine deficiency, and also has important applications in sports nutrition, anti-fatigue and weight loss fields.

[0003] Currently, there are various forms of levocarnitine preparations on the market, including tablets, capsules, injections, etc. However, these traditional dosage forms have some limitations in actual application. For example, for patients with difficulty swallowing, especially pediatric patients, ordinary tablets and capsules are inconvenient to take, which can easily cause choking and other risks; injections require professional medical personnel to operate, and may cause pain and infection at the injection site for patients, and patients need to go to medical institutions for injection, which limits the use of the scene and greatly affects the patient's medication compliance.

[0004] In the case that existing levocarnitine preparations cannot fully meet the needs of special patient groups, it is particularly urgent to develop a new and more adaptable levocarnitine dosage form. Chewable tablets, as a unique oral solid preparation, do not need to be taken with water and can be swallowed after being chewed in the mouth, which has a significant advantage for people with difficulty swallowing. Therefore, the development of levocarnitine chewable tablets has broad market prospects and important clinical significance. SUMMARY

[0005] The purpose of the present application is to provide a levocarnitine chewable tablet and a preparation method and application thereof. The levocarnitine chewable tablet provided by the present application has sustained release, palatability and high bioavailability.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions: The present application provides a levocarnitine chewable tablet, which comprises the following raw materials by weight: levocarnitine 10-20 parts, modified hydroxypropyl methylcellulose 18-25 parts, microcrystalline cellulose PH102 15-20 parts, carboxymethyl starch sodium 4-6 parts, quaternized chitosan 1-3 parts, sodium caprate 1-2 parts, sulfobutyl ether-beta-cyclodextrin 3-5 parts, mannitol 30-35 parts, sorbitol 7-13 parts, sodium stearate fumarate 0.5-1 parts and micro-powder silica 0.5-1 parts.

[0007] Preferably, the preparation method of the modified hydroxypropyl methyl cellulose comprises: mixing hydroxypropyl methyl cellulose and water to obtain a colloidal solution, adding citric acid and sodium lactate for crosslinking, adding propylene glycol, potassium carbonate and 1,2-propanediol carbonate for reaction, adding an ethanol solution for precipitation, discarding the supernatant, and obtaining the modified hydroxypropyl methyl cellulose.

[0008] More preferably, the weight ratio of the hydroxypropyl methyl cellulose, citric acid, sodium lactate, propylene glycol, potassium carbonate and 1,2-propanediol carbonate is (95-105):(2-5):(1-2):(3-8):(0.6-1.2):(15-20).

[0009] More preferably, the crosslinking temperature is 58-62℃, the pH value is 3.5-4, and the time is 2.5-3.5h.

[0010] More preferably, the reaction temperature is 65-70℃, the pH value is 8-8.5, and the time is 4.5-5.5h.

[0011] More preferably, the volume fraction of the ethanol solution is 93%-97%.

[0012] Preferably, the flavoring agent comprises one or more of strawberry flavor, peppermint flavor, citric acid and sucralose.

[0013] The application also provides a preparation method of the above-mentioned levocarnitine chewable tablet, comprising: mixing levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternized chitosan, sodium caprate and sulfobutyl ether-beta-cyclodextrin to obtain a premix; mixing modified hydroxypropyl methyl cellulose and purified water to obtain a binder solution; adding the binder solution to the premix for wet granulation, drying, adding micronized silica gel and sodium stearyl fumarate, and pressing to obtain the levocarnitine chewable tablet.

[0014] The application also provides use of the above-mentioned levocarnitine chewable tablet in the preparation of a medicament for treating diseases caused by levocarnitine deficiency.

[0015] Preferably, the diseases include chronic kidney disease, liver cirrhosis, organic aciduria, cardiomyopathy and skeletal myopathy caused by levocarnitine deficiency.

[0016] Compared with the prior art, the application has the following beneficial effects: The application provides a levocarnitine chewable tablet, which comprises levocarnitine, modified hydroxypropyl methyl cellulose, microcrystalline cellulose PH102, sodium carboxymethyl starch, quaternized chitosan, sodium caprate, sulfobutyl ether-beta-cyclodextrin, mannitol, sorbitol, sodium stearyl fumarate and micronized silica gel. The modified hydroxypropyl methyl cellulose is prepared from hydroxypropyl methyl cellulose by citric acid crosslinking and 1,2-propanediol carbonate reaction in sequence, can control the initial release of levocarnitine, slow release in the later period, and realize long-acting release of levocarnitine. The levocarnitine chewable tablet can realize stable release of levocarnitine, maintain stable blood drug concentration, has palatability and high bioavailability, is especially suitable for patients with difficulty in swallowing, and has important clinical value. DETAILED DESCRIPTION

[0017] The application provides a levocarnitine chewable tablet, which comprises the following raw materials in parts by weight: 10-20 parts of levocarnitine, 18-25 parts of modified hydroxypropyl methyl cellulose, 15-20 parts of microcrystalline cellulose PH102, 4-6 parts of sodium carboxymethyl starch, 1-3 parts of quaternized chitosan, 1-2 parts of sodium caprate, 3-5 parts of sulfobutyl ether-beta-cyclodextrin, 30-35 parts of mannitol, 7-13 parts of sorbitol, 0.5-1 part of sodium stearyl fumarate and 0.5-1 part of micronized silica gel.

[0018] The preparation method of the modified hydroxypropyl methyl cellulose preferably comprises: mixing hydroxypropyl methyl cellulose with water to obtain a colloidal solution, adding citric acid and sodium lactate for crosslinking, adding propylene glycol, potassium carbonate and 1,2-propylene glycol carbonate for reaction, then adding an ethanol solution for precipitation, discarding the supernatant, and obtaining the modified hydroxypropyl methyl cellulose. More preferably, the preparation method comprises: mixing hydroxypropyl methyl cellulose with purified water at a ratio of 1:5 g / mL, stirring and swelling at 72-78 DEG C for 45-75 min to obtain a colloidal solution (which can destroy the crystalline region of hydroxypropyl methyl cellulose, fully stretch the molecular chain, and provide active sites for subsequent chemical modification), adding citric acid and sodium lactate, crosslinking at 58-62 DEG C and a pH value of 3.5-4 for 2.5-3.5 h (carboxyl groups of citric acid are esterified with hydroxy groups of hydroxypropyl methyl cellulose, the gel strength is enhanced, a three-dimensional network structure is formed, and drug release is delayed), adding propylene glycol and potassium carbonate, adding 1,2-propylene glycol carbonate at a rate of 0.5-1 mL / min, reacting at 65-70 DEG C and a pH value of 8-8.5 for 4.5-5.5 h (this step introduces hydroxypropyl groups, adjusts the hydrophilic / hydrophobic balance, and improves the processing performance), mixing with a 93%-97% ethanol solution, precipitating at 20-25 DEG C for 28-32 min (selectively precipitating the modified hydroxypropyl methyl cellulose, removing unreacted 1,2-propylene glycol carbonate and sodium citrate byproducts), discarding the supernatant, washing the precipitate with a 65%-75% ethanol solution for 2-4 times, vacuum freeze-drying to a water content of 3 wt%-5 wt%, and obtaining the modified hydroxypropyl methyl cellulose; the weight ratio of the hydroxypropyl methyl cellulose, citric acid, sodium lactate, propylene glycol, potassium carbonate, and 1,2-propylene glycol carbonate is (95-105):(2-5):(1-2):(3-8):(0.6-1.2):(15-20); the volume ratio of the purified water and the ethanol solution is 1:1.5-2.5; and the propylene glycol is preferably 1,2-propylene glycol.

[0019] The modified hydroxypropyl methyl cellulose of the present application is modified by controllable crosslinking and hydroxypropylation, can control the diffusion rate of levocarnitine (a water-soluble molecule) through the gel layer, realize a small amount of release in the stomach and sustained release in the small intestine, enhance mucosal adhesion through electrostatic attraction between quaternized chitosan and carboxyl groups of the modified hydroxypropyl methyl cellulose, prolong the retention time of the preparation in the small intestine, improve the bioavailability of levocarnitine absorption, and form a hydrophobic cavity with sulfobutyl ether-β-cyclodextrin to enclose the hydrophobic end of levocarnitine, realize linear release, avoid peak-valley effect, reduce drug burst release, and stabilize the release rate.

[0020] The present application also comprises a flavoring agent, which preferably comprises one or more of strawberry flavor, peppermint flavor, citric acid, and sucralose.

[0021] The quaternary ammonium chitosan (purchased from Shaanxi Aibon Biological Technology Co., Ltd., item number 3589) prolongs the residence time of levocarnitine; sodium caprate enhances the penetration of levocarnitine and promotes the absorption of levocarnitine; sodium carboxymethyl starch can make the chewable tablets disperse rapidly in the oral cavity but maintain a slow-release structure; mannitol can provide a cool sweet taste and improve the tabletting flowability, and sorbitol enhances the wet feeling and can prevent moisture absorption when compounded with mannitol; sulfobutyl ether-beta-cyclodextrin can bind the hydrophobic end of levocarnitine to improve the apparent solubility; microcrystalline cellulose PH102 provides a skeleton structure to reduce the grittiness and improve the chewability; the grittiness is reduced; sodium stearyl fumarate reduces the friction and improves the tabletting flowability; and the micro-silica gel improves the particle flowability. The levocarnitine chewable tablets can achieve smooth release of levocarnitine, maintain stable blood drug concentration, improve the intestinal absorption efficiency of levocarnitine, optimize the bioavailability, optimize absorption, effectively mask the bitter taste of the drug, and improve the medication experience.

[0022] The application also provides a preparation method of the levocarnitine chewable tablets, which comprises the following steps: mixing levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-beta-cyclodextrin to obtain a premix; mixing modified hydroxypropyl methylcellulose and purified water to obtain a binder solution; adding the binder solution into the premix to wet-granulate, drying, adding micro-silica gel and sodium stearyl fumarate, and tabletting to obtain the levocarnitine chewable tablets. More preferably, the method comprises the following steps: respectively crushing levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol and sorbitol through a 50-80 mesh sieve, crushing quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-beta-cyclodextrin, and passing them through a 300-400 mesh sieve, and respectively crushing sodium stearyl fumarate and micro-silica gel through an 80-120 mesh sieve; mixing levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-beta-cyclodextrin at 50-100 rpm for 10-15 min to obtain the premix; mixing modified hydroxypropyl methylcellulose and purified water according to a weight ratio of 1:15-20, adding the premix, stirring at 200-300 rpm for 5-10 min, and then cutting for 1-3 min at 1000-1500 rpm to granulate, fluidized bed drying at 50-60 DEG C until the moisture content is 2-3 wt%, sieving through a 15-25 mesh sieve to size, mixing with micro-silica gel at 15-25 rpm for 5-10 min for lubrication, mixing with sodium stearyl fumarate at 15-20 rpm for 4-6 min, and tabletting to obtain the levocarnitine chewable tablets.

[0023] The application also provides the use of the levocarnitine chewable tablets in the preparation of a drug for treating diseases caused by levocarnitine deficiency. The diseases include chronic kidney disease, liver cirrhosis, organic aciduria, cardiomyopathy, skeletal myopathy and encephalopathy caused by levocarnitine deficiency.

[0024] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0025] Unless otherwise specified, the following embodiments are all conventional methods.

[0026] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0027] The quaternized chitosan used in the examples and comparative examples had a molecular weight of 500 kDa and a degree of substitution of 0.95. It was purchased from Shaanxi Aboni Biotechnology Co., Ltd., catalog number 3589.

[0028] Example 1 Preparation of L-carnitine chewable tablets (1) Preparation of modified hydroxypropyl methylcellulose Hydroxypropyl methylcellulose K4M was mixed with purified water at a ratio of 1:5 g / mL and stirred at 75°C for 60 min to obtain a colloidal solution. Citric acid and sodium lactate were added, and the mixture was crosslinked at 60°C and pH 3.8 for 3 h. After adding 1,2-propanediol and potassium carbonate, 1,2-propanediol carbonate was added dropwise at 0.8 mL / min. The mixture was reacted at 68°C and pH 8.2 for 5 h. The mixture was then mixed with 95% ethanol solution and precipitated at 23°C for 30 min. The supernatant was discarded, and the precipitate was washed three times with 70% ethanol solution. The precipitate was then freeze-dried under vacuum to a water content of 4 wt% to obtain modified hydroxypropyl methylcellulose. The weight ratio of hydroxypropyl methylcellulose, citric acid, sodium lactate, 1,2-propanediol, potassium carbonate, and 1,2-propanediol carbonate is 100:3:1.5:5:1:18; the volume ratio of purified water to 95% ethanol solution is 1:2.

[0029] (2) Weighing Accurately weigh the following components by weight: 15 parts L-carnitine, 20 parts modified hydroxypropyl methylcellulose, 18 parts microcrystalline cellulose PH102, 5 parts sodium carboxymethyl starch, 2 parts quaternized chitosan, 1.5 parts sodium decanoate, 4 parts sulfobutyl ether-β-cyclodextrin, 32 parts mannitol, 10 parts sorbitol, 0.8 parts sodium stearate fumarate, 0.8 parts micronized silica gel, 1 part strawberry flavor, 0.5 parts peppermint flavor, 0.8 parts citric acid, and 0.18 parts sucralose.

[0030] (3) Preparation of L-carnitine chewable tablets Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol and citric acid were respectively crushed to 60 mesh sieve, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-β-cyclodextrin were crushed to 350 mesh sieve, and sodium stearyl fumarate and silicon dioxide were respectively crushed to 100 mesh sieve; Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate, sulfobutyl ether-β-cyclodextrin and sucralose were mixed at 80 rpm for 12 min to obtain a premix; the modified hydroxypropyl methyl cellulose was mixed with purified water according to a weight ratio of 1:18, and then the premix was added, and stirring was first carried out at 250 rpm for 8 min, and then chopping was carried out at 1200 rpm for 2 min to granulate, and then fluidized bed drying was carried out at 55℃ until the moisture content was 2.5wt%, and then the granules were sieved to 20 mesh, and then silicon dioxide and strawberry flavor were added and mixed at 20 rpm for 8 min to lubricate, and then sodium stearyl fumarate and mint flavor were added and mixed at 18 rpm for 5 min, and then tabletting was carried out to obtain the levocarnitine chewable tablets.

[0031] Example 2 Preparation of levocarnitine chewable tablets (1) Preparation of modified hydroxypropyl methyl cellulose Hydroxypropyl methyl cellulose K4M was mixed with purified water according to a weight ratio of 1:4 g / mL, and then swelling was carried out by stirring at 72℃ for 75 min to obtain a colloidal solution, and then citric acid and sodium lactate were added, and then crosslinking was carried out at 58℃ and pH 3.5 for 3.5 h, and then 1,2-propanediol and potassium carbonate were added, and then 1,2-propanediol carbonate was added dropwise at a rate of 0.5 mL / min, and then reaction was carried out at 65℃ and pH 8 for 5.5 h, and then the modified hydroxypropyl methyl cellulose was obtained by mixing with a 93% ethanol solution, precipitating at 20℃ for 32 min, discarding the supernatant, washing the precipitate with a 65% ethanol solution for 2 times, and vacuum freeze-drying until the water content was 3wt%. The weight ratio of hydroxypropyl methyl cellulose, citric acid, sodium lactate, 1,2-propanediol, potassium carbonate and 1,2-propanediol carbonate was 95:2:1:3:0.6:15, and the volume ratio of the purified water and the ethanol solution was 1:2.5.

[0032] (2) Weighing Levocarnitine 10 parts, modified hydroxypropyl methyl cellulose 18 parts, microcrystalline cellulose PH102 15 parts, sodium carboxymethyl starch 4 parts, quaternary ammonium chitosan 1 part, sodium caprate 1 part, sulfobutyl ether-β-cyclodextrin 3 parts, mannitol 30 parts, sorbitol 7 parts, sodium stearyl fumarate 0.5 parts, silicon dioxide 0.5 parts, strawberry flavor 0.8 parts, mint flavor 0.3 parts, citric acid 0.5 parts and sucralose 0.1 parts were weighed according to weight parts.

[0033] (3) Preparation of levocarnitine chewable tablets Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol and citric acid were respectively crushed to 50 mesh sieve, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-β-cyclodextrin were crushed to 300 mesh sieve, sodium stearyl fumarate and fumed silica were respectively crushed to 80 mesh sieve; Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate, sulfobutyl ether-β-cyclodextrin and sucralose were mixed at 50 rpm for 15 min to obtain a premix; the modified hydroxypropyl methyl cellulose was mixed with purified water according to the weight ratio of 1:15, then the premix was added, first stirred at 200 rpm for 10 min, then chopped at 1000 rpm for 3 min to granulate, dried in a fluidized bed at 50℃ to 3wt% of moisture, sieved to 15 mesh to round, mixed with fumed silica and strawberry flavor at 15 rpm for 10 min to lubricate, mixed with sodium stearyl fumarate and peppermint flavor at 15 rpm for 6 min, then pressed to obtain the levocarnitine chewable tablets.

[0034] Example 3 Preparation of levocarnitine chewable tablets (1) Preparation of modified hydroxypropyl methyl cellulose Hydroxypropyl methyl cellulose K4M was mixed with purified water according to the weight ratio of 1:8 g / mL, stirred and swelled at 78℃ for 45 min to obtain a colloidal solution, then citric acid and sodium lactate were added, crosslinked at 62℃ and pH 4 for 2.5 h, then 1,2-propanediol and potassium carbonate were added, 1,2-propanediol carbonate was added dropwise at 1 mL / min, reacted at 70℃ and pH 8.5 for 4.5 h, then mixed with 97% ethanol solution, precipitated at 25℃ for 28 min, discarded the supernatant, washed the precipitate with 75% ethanol solution for 4 times, and vacuum freeze-dried to 5wt% of water content to obtain the modified hydroxypropyl methyl cellulose. The weight ratio of hydroxypropyl methyl cellulose, citric acid, sodium lactate, 1,2-propanediol, potassium carbonate and 1,2-propanediol carbonate was (95-105):(2-5):(1-2):(3-8):(0.6-1.2):(15-20); the volume ratio of purified water and 97% ethanol solution was 1:1.5.

[0035] (2) Weighing Levocarnitine 20 parts, modified hydroxypropyl methyl cellulose 25 parts, microcrystalline cellulose PH102 20 parts, sodium carboxymethyl starch 6 parts, quaternary ammonium chitosan 3 parts, sodium caprate 2 parts, sulfobutyl ether-β-cyclodextrin 5 parts, mannitol 35 parts, sorbitol 13 parts, sodium stearyl fumarate 1 part, fumed silica 1 part, strawberry flavor 1.5 parts, peppermint flavor 0.8 parts, citric acid 1.2 parts and sucralose 0.18 parts were accurately weighed according to the weight parts.

[0036] (3) Preparation of levocarnitine chewable tablets Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol and citric acid were respectively crushed to 80 mesh sieve, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-β-cyclodextrin were crushed to 400 mesh sieve, and sodium stearyl fumarate and silicon dioxide were respectively crushed to 120 mesh sieve; Levocarnitine, microcrystalline cellulose PH102, sodium carboxymethyl starch, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate, sulfobutyl ether-β-cyclodextrin and sucralose were mixed at 100 rpm for 10 min to obtain a premix; the modified hydroxypropyl methyl cellulose was mixed with purified water according to a weight ratio of 1:20, and then the premix was added, first stirred at 300 rpm for 5 min, and then chopped at 1500 rpm for 1 min to granulate, dried in a fluidized bed at 60°C to a moisture content of 2 wt%, sieved to 25 mesh, lubricated by mixing silicon dioxide and strawberry flavor at 25 rpm for 5 min, mixed with sodium stearyl fumarate and peppermint flavor at 20 rpm for 4 min, and then compressed to obtain levocarnitine chewable tablets.

[0037] Comparative Example 1 The specific implementation method was the same as that of Example 1, except that (1) the preparation method of the modified hydroxypropyl methyl cellulose was as follows: hydroxypropyl methyl cellulose K4M was mixed with purified water according to a weight ratio of 1:5 g / mL, and stirred and swelled at 75°C for 60 min to obtain a colloidal solution, then citric acid and sodium lactate were added, crosslinked at 60°C and pH 3.8 for 3 h, the pH value was adjusted to 7, mixed with a 95% ethanol solution, precipitated at 23°C for 30 min, the supernatant was discarded, the precipitate was washed with a 70% ethanol solution for 3 times, and vacuum freeze-dried to a water content of 4 wt% to obtain the modified hydroxypropyl methyl cellulose; The weight ratio of the hydroxypropyl methyl cellulose, citric acid and sodium lactate was 100:3:1.5; and the volume ratio of the purified water to the 95% ethanol solution was 1:2.

[0038] Comparative Example 2 The specific implementation method was the same as that of Example 1, except that (1) the preparation method of the modified hydroxypropyl methyl cellulose was as follows: hydroxypropyl methyl cellulose K4M was mixed with purified water according to a weight ratio of 1:5 g / mL, and stirred and swelled at 75°C for 60 min to obtain a colloidal solution, then 1,2-propanediol and potassium carbonate were added, 1,2-propanediol carbonate was added at a rate of 0.8 mL / min, and reacted at 68°C and pH 8.2 for 5 h, then mixed with a 95% ethanol solution, precipitated at 23°C for 30 min, the supernatant was discarded, the precipitate was washed with a 70% ethanol solution for 3 times, and vacuum freeze-dried to a water content of 4 wt% to obtain the modified hydroxypropyl methyl cellulose; The weight ratio of the hydroxypropyl methyl cellulose, 1,2-propanediol, potassium carbonate, 1,2-propanediol carbonate is 100:5:1:18; the volume ratio of the purified water to the 95% ethanol solution is 1:2.

[0039] Comparative Example 3 The specific implementation method is the same as that of Example 1, except that in step (2), the sodium carboxymethyl starch is 3.5 parts, and the quaternized chitosan is 3.5 parts.

[0040] Comparative Example 4 The specific implementation method is the same as that of Example 1, except that in step (2), the sodium carboxymethyl starch is 6 parts, and the quaternized chitosan is 1 part.

[0041] Comparative Example 5 The specific implementation method is the same as that of Example 1, except that in step (2), the sodium decanoate is 1.3 parts, and the sulfobutyl ether-β-cyclodextrin is 4.2 parts.

[0042] Comparative Example 6 The specific implementation method is the same as that of Example 1, except that in step (2), the sodium decanoate is 1.8 parts, and the sulfobutyl ether-β-cyclodextrin is 3.7 parts.

[0043] Test Example 1 Test the dissolution of levocarnitine chewable tablets According to the second method (slurry method) of Chinese Pharmacopoeia 2015 Edition Part IV General Chapter 0931, the dissolution of levocarnitine chewable tablets of Examples 1-3 and Comparative Examples 1-6 at 0.5h, 1h, 2h, 6h and 12h (cumulative dissolution) was determined, and the specific results are shown in Table 1.

[0044] The determination experiment uses pH 6.8 phosphate buffer as the dissolution medium, the mass of the levocarnitine chewable tablets to be tested is 25mg, and the dissolution medium is constant volume to 50mL, the rotation speed is 50r / min, and the detection method of levocarnitine in the solution is HPLC method.

[0045] Table 1 Dissolution of different levocarnitine chewable tablets

[0046] From Table 1, it can be seen that, in general, the dissolution of all levocarnitine chewable tablets increases with time. The 12h dissolution of the levocarnitine chewable tablets of Examples 1-3 is all above 89%, showing good sustained-release performance. From the data of Example 1 and Comparative Examples 1-2, it can be seen that double cross-linking of hydroxypropyl methyl cellulose can achieve smooth release, and only citric acid cross-linking can cause the chewable tablet to release too fast in the early stage and insufficient sustained release in the later stage, and only 1,2-propanediol carbonate cross-linking can cause the lowest dissolution throughout the process and the worst sustained-release performance, indicating that citric acid cross-linking controls the initial release, 1,2-propanediol carbonate cross-linking enhances the sustained release in the later stage, and single cross-linking causes structural defects (Comparative Example 1 is loose, and Comparative Example 2 is dense), affecting the drug release efficiency. From the data of Example 1 and Comparative Examples 3-4, it can be seen that the lower the weight ratio of carboxymethyl starch sodium and quaternized chitosan, the faster the initial release of the levocarnitine chewable tablet, and the higher the weight ratio, the slower the release, and the insufficient dissolution in the later stage.

[0047] The low initial dissolution, slow rise and high accumulation of the dissolution of the levocarnitine chewable tablets of Examples 1-3 show that the technical scheme of the present application can effectively delay the release of levocarnitine, which meets the design goal of the chewable tablet of "smooth drug release and long-acting effect", and can reduce the frequency of taking medicine and maintain stable blood drug concentration.

[0048] The above only describes the preferred embodiments of the present application, and it should be noted that, for those skilled in the art, without departing from the principles of the present application, several improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. Levocarnitine chewable tablet, characterized in that, The raw materials include the following weight parts: levocarnitine 10-20 parts, modified hydroxypropyl methylcellulose 18-25 parts, microcrystalline cellulose PH102 15-20 parts, carboxymethyl starch sodium 4-6 parts, quaternary ammonium chitosan 1-3 parts, sodium caprate 1-2 parts, sulfobutyl ether-beta-cyclodextrin 3-5 parts, mannitol 30-35 parts, sorbitol 7-13 parts, sodium stearyl fumarate 0.5-1 part, and silica gel 0.5-1 part.

2. Levocarnitine chewable tablets according to claim 1, characterized in that, The preparation method of the modified hydroxypropyl methylcellulose comprises the following steps: mixing hydroxypropyl methylcellulose and water to obtain a colloidal solution, adding citric acid and sodium lactate for crosslinking, adding propylene glycol, potassium carbonate and 1,2-propanediol carbonate for reaction, adding an ethanol solution for precipitation, and discarding the supernatant to obtain the modified hydroxypropyl methylcellulose.

3. Levocarnitine chewable tablets according to claim 2, characterized in that, The weight ratio of the hydroxypropyl methylcellulose, citric acid, sodium lactate, propylene glycol, potassium carbonate and 1,2-propanediol carbonate is (95-105):(2-5):(1-2):(3-8):(0.6-1.2):(15-20).

4. The levocarnitine chewable tablet according to claim 2, wherein The crosslinking temperature is 58-62 DEG C, the pH value is 3.5-4, and the time is 2.5-3.5 h.

5. The levocarnitine chewable tablet according to claim 2, wherein The reaction temperature is 65-70 DEG C, the pH value is 8-8.5, and the time is 4.5-5.5 h.

6. Levocarnitine chewable tablets according to claim 2, characterized in that, The volume fraction of the ethanol solution is 93%-97%.

7. Levocarnitine chewable tablets according to claim 1, characterized in that, The flavoring agent includes one or more of strawberry flavor, peppermint flavor, citric acid, and sucralose.

8. A process for the preparation of levocarnitine chewable tablets according to any one of claims 1-7, characterized by, The preparation method comprises the following steps: Levocarnitine, microcrystalline cellulose PH102, carboxymethyl starch sodium, mannitol, sorbitol, quaternary ammonium chitosan, sodium caprate and sulfobutyl ether-beta-cyclodextrin are mixed to obtain a premix; modified hydroxypropyl methylcellulose and purified water are mixed to obtain a binder solution; the binder solution is added to the premix for wet granulation, dried, and then mixed with silica gel and sodium stearyl fumarate to obtain levocarnitine chewable tablets.

9. Use of the levocarnitine chewable tablets according to any one of claims 1-7 in the preparation of a medicament for treating diseases caused by levocarnitine deficiency.

10. Use according to claim 9, characterized in that, The diseases include chronic kidney disease, liver cirrhosis, organic aciduria, cardiomyopathy, skeletal myopathy and encephalopathy caused by levocarnitine deficiency.

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