Acetylcysteine water-free swallowing granules and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and relates to acetylcysteine anhydrous swallowing granules and a preparation method thereof. The acetylcysteine water-free swallowing particle disclosed by the invention is composed of a drug-loading particle and a taste-modifying particle. The drug-loaded particles comprise the following components in percentage by weight: 50.0-95.0% of acetylcysteine, 0.5-20.0% of adhesive and 0-49.5% of filler, the adhesive is selected from a low-melting-point adhesive, the filler is selected from a low-melting-point adhesive, the filler is selected from a low-melting-point adhesive, and the adhesive is selected from a low-melting-point adhesive, a high-melting-point adhesive, a high-melting-point adhesive and a high-melting-point adhesive. The low-melting-point adhesive is preferably selected from one or a mixture of more than two of lauric acid polyethylene glycol glyceride, glyceryl monostearate and glyceryl distearate, polyethylene glycol 4000 and polyoxyethylene 40. The acetylcysteine water-free swallowing granules prepared by the invention are convenient to carry, can be rapidly disintegrated in the oral cavity and rapidly release medicines, enter gastrointestinal tracts along with swallowing actions to be absorbed, and do not need to be swallowed by water; the preparation is good in medicine taking compliance, stable in quality, rapid in effect taking and convenient to take.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and specifically to an anhydrous acetylcysteine ​​granule and its preparation method. Background Technology

[0002] Acetylcysteine, a white crystalline powder, also known as N-acetyl-L-cysteine, has the chemical formula C5H9NO3S and a relative molecular mass of 163.195. It is readily soluble in water and ethanol, with a melting point between 106 and 108°C and a boiling point of 407.7°C. It is a mucolytic agent with strong expectorant properties. The sulfhydryl groups in its molecule can break the disulfide bonds in the glycoprotein polypeptide chains of sputum, thereby reducing the viscosity of the sputum and making it easier to cough up. It can also break the DNA fibers in purulent sputum. Therefore, it can dissolve not only white viscous sputum but also purulent sputum. For patients who do not respond to general expectorants, this product is significantly effective.

[0003] Anhydrous Swallowing Granules are a type of granule that can be swallowed without water. In addition to the efficacy of the medication, they offer the advantages of being anhydrous: upon contact with saliva, they rapidly dissolve and dissolve, simultaneously stimulating the mouth to produce a large amount of saliva, allowing the medication to dissolve better and propelling it into the digestive tract, achieving the purpose of waterless administration. This is especially suitable for people with swallowing difficulties. Their short disintegration time, rapid dissolution rate, convenient administration, and high bioavailability improve patient compliance. Furthermore, due to their good taste-masking effect, they are also suitable for children.

[0004] Anhydrous granules eliminate the risk of oral blockage or choking associated with conventional oral preparations, improving medication safety for special patients and some bedridden patients. They also retain the advantages of traditional oral solid dosage forms: lightweight and portable packaging, accurate dosage, high stability, and no need for water or secondary containers, making them suitable for travel and special situations such as motion sickness, allergic reactions, coughs, or asthma. When placed in the mouth, they dissolve rapidly with saliva, providing immediate relief. Furthermore, they have a pleasant taste, no granular feel, short oral retention time, and minimal oral residue after administration.

[0005] Existing anhydrous granule preparation processes mostly involve coating microspheres with a drug-containing layer, an isolation layer, a smoothing layer, and flavoring granules. Among these processes, microsphere coating involves multiple coating steps, making the overall process more complex and limiting the drug loading capacity due to process limitations. In addition, there are related patents on wet granulation or extrusion spheronization processes. Although these processes are relatively common, they are also limited by process limitations, resulting in a relatively limited drug loading capacity. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, this invention provides anhydrous granules that are simple to prepare, have high formulation stability, fast dissolution rate, high drug loading capacity, and good taste-enhancing effect. The formulation has a good taste and good patient compliance, and can be basically completely dissolved within 5 minutes with a dissolution rate of over 90%. It can be swallowed directly, which increases the medication compliance and safety of elderly and infant patients. It is convenient to take, has good efficacy, and improves the clinical value of the drug.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] An anhydrous acetylcysteine ​​granule is composed of drug-loaded granules and flavoring granules, wherein the mass ratio of the drug-loaded granules to the flavoring granules is 1:0.5 to 1:25.

[0009] The drug-loaded particles comprise the following components: acetylcysteine, filler, and binder. The weight percentage of each component in the drug-loaded particles is as follows: acetylcysteine ​​50.0%–95.0%, binder 0.5%–20.0%, and filler 0%–49.5%. The binder is selected from low-melting-point binders.

[0010] Furthermore, the weight percentage of each component in the drug-loaded particles is as follows: acetylcysteine ​​60.0%–80.0%, binder 5.0%–15.0%, and the remainder is filler.

[0011] The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol and maltitol; preferably a mixture of maltitol, lactose and maltitol.

[0012] The low-melting-point adhesive is selected from one or more of the following: polyoxyethylene 35, polyoxyethylene 40, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polyethylene glycol glycerol laurate, cetyl alcohol, octadecyl alcohol, polyethylene glycol 6000, polyethylene glycol 4000, polyethylene glycol 3000, polyethylene glycol 2000, polyethylene glycol 1500, glyceryl mono- and glyceryl di-stearate, and glyceryl palmitate stearate.

[0013] Furthermore, the low-melting-point adhesive is preferably one or a mixture of two or more of polyethylene glycol glycerol laurate, glycerol mono- and glycerol di-stearate, polyethylene glycol 4000, and polyethylene oxide 40.

[0014] Preferably, the drug-loaded particles comprise acetylcysteine, a filler, and a low-melting-point binder, with each component comprising the following weight percentages of the drug-loaded particles: acetylcysteine: 60.0-80.0%, filler: 10.0-30.0%, and low-melting-point binder: 5.0-15.0%.

[0015] More preferably, the weight percentage of each component in the drug-loaded particles is as follows: acetylcysteine: 65.0-70.0%, filler: 20.0-27.0%, and low-melting-point binder: 8.0-10.0%.

[0016] The filler is one or both of lactose and maltitol.

[0017] When the filler is a mixture of lactose and maltitol, the mass ratio of lactose to maltitol is 1:2.

[0018] The low-melting-point adhesive is one or both of polyethylene glycol glycerol laurate and polyoxyethylene 40.

[0019] When the low-melting-point adhesive is a mixture of polyethylene glycol glycerol laurate and polyethylene oxide 40, the mass ratio of polyethylene glycol glycerol laurate to polyethylene oxide 40 is 2:3 to 3:1.

[0020] The flavoring granules contain the following components: filler, sweetener, acidulant, and flavoring, with the following weight percentages: filler 85.2–98.9%, sweetener 0.6–8.0%, acidulant 0.4–6.0%, and flavoring 0.1–0.8%.

[0021] The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl methylcellulose and maltitol.

[0022] The filler is preferably one or a mixture of two of maltitol and hydroxypropyl methylcellulose;

[0023] When the filler is a mixture of maltitol and hydroxypropyl methylcellulose, maltitol accounts for 75.0% to 85.0% of the filler.

[0024] The sweetener is selected from one or more of the following: stevioside, triclolitol, mannitol, lactitol, erythritol, aspartame, sucrose, sorbitol, glucono-δ-lactone, neotame, and glycyrrhizin. Preferably, it is a mixture of one or more of the following: glycyrrhizin, erythritol, and neotame.

[0025] The acidulant is selected from one or more of citric acid, lactic acid, malic acid, tartaric acid, and fumaric acid. Preferably, it is a mixture of one or more of fumaric acid and malic acid.

[0026] The flavoring is selected from one or more of the following: orange flavoring, tangerine flavoring, lemon flavoring, cream flavoring, vanilla flavoring, chocolate flavoring, almond flavoring, strawberry flavoring, cherry flavoring, blueberry flavoring, peach flavoring, apple flavoring, banana flavoring, watermelon flavoring, and cola flavoring. Preferably, it is a mixture of one or more of the following: lemon flavoring, cherry flavoring, and peach flavoring.

[0027] Preferably, the flavoring granules are composed of the following:

[0028] Glycyrrhizin 0.5–5.0%, erythritol 0.1–3.0%, fumaric acid 0.1–3.0%, malic acid 0.3–3.0%, lemon flavor 0.1–0.8%, maltitol 85.2–98.9%.

[0029] More preferably, glycyrrhizin 1.5–4.0%, erythritol 0.5–2.5%, fumaric acid 0.7–2.0%, malic acid 0.5–2.0%, lemon flavor 0.3–0.5%, and maltitol 89.0–96.5%.

[0030] Furthermore, the present invention provides a method for preparing the anhydrous acetylcysteine ​​granules:

[0031] (1) Preparation of drug-loaded particles:

[0032] Acetylcysteine, binder, and filler are weighed and mixed evenly according to the prescription, heated together, and then sheared and granulated using a hot melt granulator to produce drug-loaded granules.

[0033] When the heating temperature is ±10℃ of the melting point of the low-melting-point adhesive, the adhesive approaches or reaches the melting temperature, and part or all of the adhesive melts. After changing from solid to liquid, it is combined with acetylcysteine ​​and fillers to form drug-loaded particles.

[0034] (2) Preparation of flavoring granules:

[0035] Fillers, sweeteners, acidulants, and flavorings are weighed and mixed evenly according to the prescription. A binder solution of a certain concentration is added, and granules are obtained by stirring and shearing.

[0036] The adhesive is polyvinylpyrrolidone K30, and the concentration of polyvinylpyrrolidone K30 is 2% to 10%.

[0037] Specifically, this invention proposes a method for preparing anhydrous oral granules using a hot-melt granulation process, the steps of which are as follows:

[0038] (1) Weigh out the prescribed amount of acetylcysteine, filler, and binder for the drug-loaded granules and mix them evenly in a hot melt granulator;

[0039] (2) Heat the uniformly mixed solid powder to 65±10℃ and prepare a soft material in the molten state;

[0040] (3) Cut and granulate the soft material obtained in step (2), and sieve it to prepare drug-loaded particles;

[0041] (4) Weigh out the filler, sweetener, acidulant and flavoring of the flavoring granule prescription and mix them evenly;

[0042] (5) Add an appropriate amount of adhesive aqueous solution to the mixture obtained in step (4), cut and granulate, and sieve to prepare flavored granules;

[0043] (6) Mix the drug-loaded granules obtained in step (3) and the flavoring granules obtained in step (5) evenly to obtain the final product.

[0044] Low-melting-point binders are the most important excipients for anhydrous oral granules. Since the drug granules contain no wetting agents, the uniform bonding of the drug powder and other excipients mainly relies on the low-melting-point binder, which melts upon heating to wet and bind the other powders, achieving the granulation effect. Therefore, low-melting-point binders must be selected to avoid damage to the drug due to excessively high heating temperatures. Anhydrous oral granules are characterized by being directly swallowable, non-toxic, having good compatibility, easy mixing with drugs, and facilitating drug release. Furthermore, the resulting anhydrous oral granules possess a certain degree of mechanical strength to prevent breakage during transportation and handling.

[0045] The anhydrous acetylcysteine ​​granules prepared by this invention are convenient to carry, rapidly disintegrate in the oral cavity, and quickly release the drug. They are absorbed into the gastrointestinal tract with swallowing, eliminating the need for water. This formulation exhibits good patient compliance, making it particularly suitable for patients with swallowing difficulties. Furthermore, this dosage form is stable in quality, provides accurate dosage, and has a rapid onset of action, solving the problems of slow onset and inconvenience associated with ordinary tablets. The anhydrous granules of this invention require small amounts of excipients, have a simple preparation process, and low cost, resulting in considerable economic and social benefits. Attached Figure Description

[0046] Figure 1 The dissolution curves of the drug-loaded particles in Examples 7-12 are shown in the figures for 1-5 min. Detailed Implementation

[0047] Example 1: Selection of Filler Type in Drug-Loaded Particles

[0048] Using polyethylene glycol glycerol laurate as a low-melting-point binder, the effects of different fillers on the particle size, dissolution time, and dissolution rate of drug-loaded particles were investigated.

[0049] prescription

[0050]

[0051] The preparation method is as follows:

[0052] (1) Mix the weighed raw and auxiliary materials thoroughly to ensure that the low-melting-point adhesive is mixed evenly;

[0053] (2) The solid mixture obtained in step (1) is placed in a hot melt granulator for hot melt granulation, and the heating temperature is 65°C;

[0054] (3) The hot melt particles obtained in step (2) are granulated by an online granulation device to obtain the final product.

[0055] The dissolution test methods and conditions are as follows:

[0056] The determination was performed using the paddle method, with 900 ml of pH 1.0 hydrochloric acid solution as the dissolution medium at a temperature of 37°C and a rotation speed of 50 rpm. Samples were taken at 1, 2, 3, 4, and 5 minutes. The dissolution solution was filtered, and 2 ml of the initial filtrate was discarded. 3 ml of the subsequent filtrate was accurately measured and placed in a 10 ml volumetric flask. The solution was diluted to the mark with the dissolution medium to obtain the test solution, and the absorbance of the sample was measured.

[0057] Table 1. Screening of Filler Types

[0058]

[0059] As can be seen from Table 1, the amount of fine powder produced by using maltitol alone is the lowest, the particles are more uniform, and the dissolution time is within 25 seconds, with a dissolution rate of more than 95% at 5 minutes.

[0060] Experiments were conducted to mix other fillers with maltitol in a 1:2 ratio, but no filler combination was found to be superior to the formulation consisting entirely of maltitol in terms of particle size distribution, dissolution time, and dissolution rate. The results are shown in Table 2.

[0061] Table 2 Screening of maltitol with other fillers

[0062]

[0063] As shown in Table 2, the fine powder content of other fillers combined with maltitol is less than 6%, the dissolution time is less than 30 seconds, and the dissolution rate is greater than or equal to 95% at 5 minutes. However, the combined fillers do not show better performance in terms of particle size, solubility, and dissolution rate than the formulation with maltitol as the sole filler. Therefore, maltitol is preferred as the filler.

[0064] Example 2: Screening of filler dosage

[0065]

[0066] Table 3 Screening of Maltitol Dosage

[0067]

[0068] As can be seen from Table 3, when the amount of maltitol is 25%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 23s. The dissolution rate at 5min is 99%, which is greater than 95%. However, when the amount of sucrose is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min in the medium is not much different, but both are less than the dissolution rate when the amount of sucrose is 25%.

[0069] Therefore, when the sucrose content is 15-25%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0070] Table 4 Screening of Mannitol Dosage

[0071]

[0072]

[0073] As can be seen from Table 4, when the amount of mannitol is 25%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 25s. The dissolution rate at 5min is 99%, which is greater than 95%. However, when the amount of mannitol is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min is not significantly different, but both are lower than the dissolution rate when the amount of mannitol is 25%.

[0074] Therefore, when the amount of mannitol is 20-25%, a drug-loaded particle with good particle size, dissolution time and dissolution rate can be obtained.

[0075] Table 5 Screening of lactose dosage

[0076]

[0077] As can be seen from Table 5, when the amount of lactose is 20%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 23s. The dissolution rate at 5min is 99%, which is greater than 95%. However, when the amount of lactose is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min is not significantly different.

[0078] Therefore, when the lactose content is 15-25%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0079] Example 3: Screening of binders in drug-loaded particles

[0080] prescription:

[0081]

[0082] The preparation method is as follows:

[0083] (1) Mix the weighed raw and auxiliary materials thoroughly to ensure that the low-melting-point adhesive is mixed evenly;

[0084] (2) The solid mixture obtained in step (1) is placed in a hot melt granulator for hot melt granulation, and the heating temperature is 60°C;

[0085] (3) The hot melt particles obtained in step (2) are granulated by an online granulation device to obtain the final product.

[0086] Table 6 Screening of Low Melting Point Adhesives

[0087]

[0088] Table 7 Screening of Low Melting Point Adhesive Combinations

[0089]

[0090] As can be seen from Table 6, the amount of fine powder produced by using either polyethylene glycol glycerol laurate or polyoxyethylene 40 alone is the lowest, the particles are more uniform, and the dissolution time is within 25 seconds, with a dissolution rate of more than 95% at 5 minutes.

[0091] Since polyethylene glycol glycerol laurate and polyoxyethylene 40 have different melting points, we expect to obtain better particle size, dissolution time and dissolution rate by adjusting the combination ratio, in order to obtain a drug-loaded particle with better particle size, dissolution time and dissolution rate than an anhydrous oral granule prepared by a single low melting point binder.

[0092] The ratio of polyethylene glycol glycerol laurate to polyoxyethylene 40 was varied, and the results are shown in Table 8.

[0093] Table 8 Screening of the ratio of polyethylene glycol glycerol laurate to polyoxyethylene 40

[0094]

[0095] As shown in Table 8, when polyethylene glycol glycerol laurate and polyoxyethylene 40 are mixed in a mass ratio of 1:6 to 6:1, the dissolution time is less than 30 seconds, and the dissolution rate is greater than 90% within 5 minutes, but the particle size varies considerably. When the ratio is 2:3 to 3:1, not only is the particle size better and there is less fine powder, but the dissolution time is also less than 25 seconds, and the dissolution rate is greater than 95% within 5 minutes. Especially when the ratio is 3:1 to 3:2, there is the least fine powder, and the dissolution time is significantly less than or equal to that of drug-loaded particles prepared using polyethylene glycol glycerol laurate or polyoxyethylene 40 alone, with complete dissolution achieved within 5 minutes.

[0096] Example 4: Screening of the amount of low-melting-point binder in drug-loaded particles

[0097] Using polyethylene glycol glycerol laurate, glycerol mono- and glycerol distearate, polyethylene glycol 4000, polyoxyethylene 40, or a mixture of two of these as a low-melting-point binder

[0098] prescription

[0099]

[0100] The preparation method is as follows:

[0101] (1) Mix the weighed raw and auxiliary materials thoroughly to ensure that the low-melting-point adhesive is mixed evenly;

[0102] (2) The solid mixture obtained in step (1) is placed in a hot melt granulator for hot melt granulation, and the heating temperature is 60°C;

[0103] (3) The hot melt particles obtained in step (2) are granulated by an online granulation device to obtain the final product.

[0104] Table 9 Screening of Polyethylene Glyceryl Laurate Dosage

[0105]

[0106] As shown in Table 9, when the dosage of polyethylene glycol glycerol laurate is 5-15%, the proportion of fine powder is less than 8%, the dissolution time is less than 30 seconds, and the dissolution rate is greater than 90%. When the dosage is 8-12%, the amount of fine powder is lower, the particles are more uniform, and the dissolution time is shorter, all less than 25 seconds, with a dissolution rate of greater than 95% at 5 minutes. However, when the dosage of polyethylene glycol glycerol laurate is increased or decreased, the amount of fine powder increases and the uniformity of particles decreases.

[0107] Therefore, when the amount of polyethylene glycol glycerol laurate is 8-12%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0108] Table 10 Screening of Polyoxyethylene 40 Dosage

[0109]

[0110]

[0111] As shown in Table 10, when the dosage of polyoxyethylene 40 is 5-15%, the proportion of fine powder is less than 7%, the dissolution time is less than 30 seconds, and the dissolution rate is above 90% within 5 minutes. When the dosage is 8-12%, the proportion of fine powder is less than 5%, the dissolution time is less than 25 seconds, and the dissolution rate is above 95% within 5 minutes.

[0112] Therefore, when the amount of polyoxyethylene 40 is 8-12%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0113] Table 11 Screening of the dosage of glyceryl monostearate and glyceryl distearate

[0114]

[0115] As shown in Table 11, when the dosage of glyceryl monostearate and glyceryl distearate is 5-10%, the proportion of fine powder is less than 5.0%, the dissolution time is less than 25 seconds, and the dissolution rate is greater than 95%. When the dosage of glyceryl monostearate and glyceryl distearate is 5%, the proportion of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 23 seconds, with a dissolution rate of 97% at 5 minutes.

[0116] Therefore, when the amount of mono- and di-stearate glycerides is 5-10%, a drug-loaded particle with better particle size, dissolution time, and dissolution rate can be obtained.

[0117] Table 12 Screening of total dosage when the ratio of polyethylene glycol glycerol laurate to polyoxyethylene 40 is 3:1

[0118]

[0119] As can be seen from Table 12, when the ratio of polyethylene glycol glycerol laurate to polyoxyethylene 40 is fixed at 3:1, and the total amount of low melting point binder is 8%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter at 19s, with a 5-minute dissolution rate of 99%. However, when the total amount of both is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the 5-minute dissolution rate does not differ much.

[0120] Therefore, when the ratio of polyethylene glycol glycerol laurate to polyoxyethylene 40 is fixed at 3:1 and the total amount of both is 8-12%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0121] From Tables 9-12, it can be concluded that when the low-melting-point adhesive content is 5-15%, the fine powder particle size, dissolution time, and 5-minute dissolution rate are all good. When glyceryl laurate, glyceryl mono- and glyceryl di-stearate, and polyoxyethylene 40 are used as low-melting-point adhesives individually, the preferred dosage of each component is: glyceryl laurate 8-12%, polyoxyethylene 40 8-12%, and glyceryl mono- and glyceryl di-stearate 5-10%. When glyceryl laurate and polyoxyethylene 40 are mixed in a 3:1 ratio as a low-melting-point adhesive, the preferred dosage is 8-12%.

[0122] Example 5: Screening of Flavoring Granular Fillers:

[0123]

[0124] The preparation method is as follows:

[0125] (1) Weigh out the prescribed amounts of filler, sweetener, acidulant and flavoring and mix them evenly;

[0126] (2) Add an appropriate amount of adhesive to the mixture obtained in step (1), cut and granulate, and sieve to prepare flavored granules.

[0127] Table 13 Screening of Flavoring Granular Fillers

[0128]

[0129] The results showed that the addition of various fillers improved patients' comfort during administration, with sucrose or maltitol providing the best comfort.

[0130] Example 6: Screening of types of flavoring granules sweeteners and acidulants:

[0131]

[0132] The preparation method is the same as in Example 5.

[0133] Table 14 Screening of flavoring granules for sweeteners and acidulants

[0134]

[0135]

[0136] Adding different acidulants and sweeteners can improve the overall comfort of patients. The best overall comfort is achieved when glycyrrhizin and erythritol are mixed in a 1:1 ratio as sweeteners and fumaric acid and malic acid are mixed in a 1:1 ratio as acidulants.

[0137] Example 7: Preparation of anhydrous acetylcysteine ​​granules

[0138] (1) Preparation of drug-loaded particles:

[0139] prescription

[0140] Composition and dosage

[0141] Acetylcysteine ​​200.0 mg (90%)

[0142] The preparation method of 22.2 mg (10%) of polyethylene glycol laurate was the same as in Example 1.

[0143] (2) Preparation of flavoring granules:

[0144] prescription

[0145]

[0146] The preparation method is the same as in Example 5.

[0147] (3) Mix the drug-loaded granules and flavoring granules at a ratio of 1:0.5.

[0148] Example 8: Preparation of anhydrous acetylcysteine ​​granules

[0149] (1) Preparation of drug-loaded particles:

[0150] prescription:

[0151]

[0152] The preparation method is the same as in Example 1.

[0153] (2) Preparation of flavoring granules:

[0154] prescription:

[0155]

[0156] The preparation method is the same as in Example 5.

[0157] (3) Mix the drug-loaded granules and flavoring granules at a ratio of 1:25.

[0158] Example 9: Preparation of anhydrous acetylcysteine ​​granules

[0159] (1) Preparation of drug-loaded particles:

[0160] prescription:

[0161]

[0162] The preparation method is the same as in Example 1.

[0163] (2) Preparation of flavoring granules:

[0164] prescription:

[0165]

[0166] (3) The drug-loaded granules and flavoring granules were mixed in a 1:5 ratio. Example 10 Preparation of anhydrous acetylcysteine ​​granules (1) Preparation of drug-loaded granules:

[0167] prescription:

[0168]

[0169] The preparation method is the same as in Example 1.

[0170] (2) Preparation of flavoring granules:

[0171] prescription:

[0172]

[0173] The preparation method is the same as in Example 5.

[0174] (3) The drug-loaded granules and flavoring granules were mixed at a ratio of 1:10. Example 11 Preparation of anhydrous acetylcysteine ​​granules (1) Preparation of drug-loaded granules:

[0175] prescription:

[0176]

[0177] The preparation method is the same as in Example 1.

[0178] (2) Preparation of flavoring granules:

[0179] prescription:

[0180]

[0181] The preparation method is the same as in Example 5.

[0182] (3) The drug-loaded granules and flavoring granules were mixed at a ratio of 1:10. Example 12 Preparation of anhydrous acetylcysteine ​​granules (1) Preparation of drug-loaded granules:

[0183] prescription:

[0184]

[0185] The preparation method is the same as in Example 1.

[0186] (2) Preparation of flavoring granules:

[0187] prescription:

[0188]

[0189]

[0190] The preparation method is the same as in Example 5.

[0191] (3) Mix the drug-loaded granules and flavoring granules at a ratio of 1:10.

[0192] Properties of the anhydrous acetylcysteine ​​granules from Examples 7-12 in Example 13:

[0193] Table 15 Properties of the anhydrous swallowable granules in Examples 7-12

[0194]

[0195] Table 16. Taste and comfort of use in Examples 7-12

[0196]

Claims

1. An anhydrous acetylcysteine ​​granule, comprising drug-loaded granules and flavoring granules, characterized in that, The drug-loaded particles comprise the following components: acetylcysteine, filler, and binder. The weight percentage of each component in the drug-loaded particles is as follows: acetylcysteine ​​50.0%–95.0%, binder 0.5%–20.0%, and filler 0%–49.5%. The binder is a low-melting-point binder.

2. The anhydrous acetylcysteine ​​granules as described in claim 1, characterized in that, The weight percentage of each component in the drug-loaded particles is as follows: acetylcysteine ​​60.0-80.0%, binder 5.0%-15.0%, filler: 10.0-30.0%; more preferably acetylcysteine. Cysteine: 65.0–70.0%, Filler: 20.0–27.0%, Adhesive: 8.0%–10.0%.

3. The anhydrous acetylcysteine ​​granules as described in claim 1 or 2, characterized in that, The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol and maltitol; the low-melting-point binder is selected from one or more of polyethylene oxide 35, polyethylene oxide 40, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, polyethylene glycol glycerol laurate, cetyl alcohol, octadecyl alcohol, polyethylene glycol 6000, polyethylene glycol 4000, polyethylene glycol 3000, polyethylene glycol 2000, polyethylene glycol 1500, glyceryl mono- and di-stearates, and glyceryl stearate palmitate.

4. The anhydrous acetylcysteine ​​granules as described in claim 1 or 2, characterized in that, The low-melting-point adhesive is selected from one or more of polyethylene glycol glycerol laurate, glycerol mono- and di-stearate, polyethylene glycol 4000, and polyoxyethylene 40; the filler is one or two of lactose and maltitol.

5. The anhydrous acetylcysteine ​​granules as described in claim 4, characterized in that, When the low-melting-point adhesive is a mixture of polyethylene glycol glycerol laurate and polyethylene oxide 40, the mass ratio of polyethylene glycol glycerol laurate to polyethylene oxide 40 is 2:3 to 3:

1.

6. The anhydrous acetylcysteine ​​granules as described in claim 4, characterized in that, When the filler is a mixture of lactose and maltitol, the mass ratio of lactose to maltitol is 1:

2.

7. The anhydrous acetylcysteine ​​granules as described in claim 1, characterized in that, The flavoring granules contain the following components: filler, sweetener, acidulant, and flavoring, with the following weight percentages: filler 85.2–98.9%, sweetener 0.6–8.0%, acidulant 0.4–6.0%, and flavoring 0.1–0.8%.

8. The anhydrous acetylcysteine ​​granules as described in claim 7, characterized in that, The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl methylcellulose, and maltitol; the sweetener is selected from one or more of steviol, triclolitol, mannitol, lactitol, erythritol, aspartame, sucrose, sorbitol, glucono-δ-lactone, neotame, and glycyrrhizin. Preferably, it is a mixture of one or more of glycyrrhizin, erythritol, and neotame; the acidulant is selected from one or more of citric acid, lactic acid, malic acid, tartaric acid, and fumaric acid; the flavoring is selected from one or more of orange flavoring, tangerine flavoring, lemon flavoring, cream flavoring, vanilla flavoring, chocolate flavoring, almond flavoring, strawberry flavoring, cherry flavoring, blueberry flavoring, peach flavoring, apple flavoring, banana flavoring, watermelon flavoring, and cola flavoring.

9. The anhydrous acetylcysteine ​​granules as described in claim 1, characterized in that, Its preparation method includes the following steps: (1) Preparation of drug-loaded particles: Acetylcysteine, binder, and filler are weighed and mixed evenly according to the prescription, heated together, and then sheared and granulated using a hot melt granulator to produce drug-loaded granules. (2) Preparation of flavoring granules.

10. The use of the anhydrous acetylcysteine ​​granules of claim 1 in the preparation of expectorant drugs.

Images