An ibuprofen anhydrous swallow granule and a preparation method thereof

Abstract

The present application relates to the field of medicine, and relates to a kind of ibuprofen anhydrous swallowing granules and preparation method thereof.The ibuprofen anhydrous swallowing granules are composed of drug-loaded granules and flavoring granules.The drug-loaded granules contain the following components: ibuprofen, filler, disintegrant, binder, and the weight percentage of each component in the drug-loaded granules is as follows: ibuprofen 50.0-95.0%, disintegrant 0-20.0%, binder 0.5%-25.0%, and filler 0-50.0%.The mass ratio of ibuprofen: disintegrant: binder is 80-90: 0-10: 5-20.The binder is selected from low-melting-point binders.The drug-loaded granules are granulated using a hot-melt granulator, and then mixed with the flavoring granules.The ibuprofen anhydrous swallowing granules prepared by the present application are convenient to carry, can quickly disintegrate in the oral cavity, rapidly release the drug, and be absorbed into the gastrointestinal tract with the swallowing action, without the need for water to swallow.The formulation has good medication compliance, and is particularly suitable for patients with swallowing difficulties.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and specifically to an anhydrous ibuprofen granules and a method for preparing the same. Background Technology

[0002] Ibuprofen is a white crystalline or powdery substance, chemically named 2-(4-isobutylphenyl)-propionic acid, also known as isobutylprofen or isobutylphenylpropionic acid, with the chemical formula C64-2H2O. 13 H 18 O2 has a relative molecular mass of 206.28. It is readily soluble in NaOH, Na2CO3, ethanol, acetone, chloroform, etc., but almost insoluble in water. Its melting point is between 74.5 and 77.5℃.

[0003] Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to relieve mild to moderate pain and inflammation, and is widely used in the treatment of various types of pain and inflammation. Ibuprofen's mechanism of action primarily involves reducing pain and inflammation by inhibiting the synthesis of prostaglandins. Prostaglandins are chemical substances in the human body; when the body is stimulated by infection or inflammation, prostaglandin levels increase, leading to increased pain and inflammation. Ibuprofen can inhibit prostaglandin synthesis, thereby reducing pain and inflammation. In addition, ibuprofen can also reduce prostaglandin synthesis by inhibiting the activity of cyclooxygenase. Cyclooxygenase is an enzyme that converts arachidonic acid into prostaglandins and other chemical substances. Ibuprofen can inhibit the activity of cyclooxygenase, thereby reducing prostaglandin synthesis.

[0004] Anhydrous Swallowing Granules are granules that can be swallowed without water. While retaining the effects of medication, they also offer the advantages of being anhydrous: they rapidly disintegrate and dissolve upon contact with saliva, simultaneously stimulating the mouth to secrete a large amount of saliva to further dissolve the drug and propel it into the digestive tract, allowing for waterless administration. This makes them particularly suitable for people with swallowing difficulties. They also feature short disintegration time, rapid dissolution, convenient administration, and high bioavailability, improving patient compliance. Furthermore, their good taste-masking effect makes them suitable for children.

[0005] Anhydrous granules eliminate the risk of oral blockage or choking associated with conventional oral medications, improving medication safety for special patients such as children, the elderly, psychiatric 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 upon contact with saliva, providing immediate relief. Furthermore, they have a pleasant taste, no granular feel, short oral retention time, and minimal oral residue.

[0006] 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

[0007] 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, with a dissolution rate of over 90% within 5 minutes, or even complete dissolution, and can be swallowed directly. This increases the medication compliance and safety of elderly and infant patients, makes it convenient to take, has good efficacy, and can improve the clinical value of the drug.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] An anhydrous ibuprofen granule, consisting of drug-loaded granules and flavoring granules.

[0010] The drug-loaded particles comprise the following components: ibuprofen, filler, disintegrant, and binder, with each component accounting for the following weight percentages of the drug-loaded particles: ibuprofen 50.0%–95.0%, disintegrant 0%–20.0%, binder 0.5%–25.0%, and filler 0%–50.0%.

[0011] Furthermore, the weight percentage of each component in the drug-loaded particles is as follows: ibuprofen 65.0-70.0%, disintegrant 2.0-8.0%, binder 4.0%-16.0%, and the remainder is filler.

[0012] The mass ratio of ibuprofen: disintegrant: binder is 80-90:0-10:5-20, preferably 80-90:0-10:10-15, and more preferably 80:5-10:10-15.

[0013] The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, and starch; preferably one or two of sucrose and mannitol.

[0014] The disintegrant is selected from one or a mixture of two or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose. Preferably, it is one or two of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

[0015] The adhesive is selected from low-melting-point adhesives, wherein 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.

[0016] Furthermore, the low-melting-point adhesive is preferably one or a mixture of two or more of poloxamer 188, cetyl alcohol, polyethylene glycol 4000, and octadecyl alcohol.

[0017] Preferably, the drug-loaded particles comprise ibuprofen, sucrose, sodium carboxymethyl starch, and a low-melting-point binder, with each component accounting for the following weight percentage of the drug-loaded particles: ibuprofen 65.0-70.0%, sodium carboxymethyl starch 2.0-8.0%, low-melting-point binder 4.0-16.0%, and the remainder being sucrose.

[0018] The low-melting-point adhesive is one or a mixture of two or more of cetyl alcohol and polyethylene glycol 4000.

[0019] When the low-melting-point binder is a mixture of hexadecyl alcohol and polyethylene glycol 4000, the mass ratio of hexadecyl alcohol to polyethylene glycol 4000 is 1:4 to 4:1, preferably 2:1 to 3:1.

[0020] The flavoring granules contain the following components: filler, sweetener, acidulant, and flavoring, with the following weight percentages: filler 88.0%–99.7%, sweetener 0.1%–8.0%, acidulant 0.1%–3.0%, and flavoring 0.1%–1.0%.

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

[0022] The filler is preferably one or a mixture of two or more of sucrose and mannitol;

[0023] When the filler is a mixture of sucrose and mannitol, sucrose accounts for 70.0% to 98.0% of the filler.

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

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

[0028] Neotame 0.1–10.0%, sweet orange flavor 0.1–3.0%, stevioside 0.1–10.0%, citric acid 0.1–10.0%, triclolitol 0.1–10.0%, malic acid 0.1–10.0%, sucrose 47.0–99.5%.

[0029] More preferably, neotame 0.3–6.0%, sweet orange flavor 0.1–1.0%, stevioside 0.3–8.0%, citric acid 0.1–3.0%, triclolitol 0.3–6.0%, malic acid 0.1–3.0%, and sucrose 74.0–98.8%.

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

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

[0032] Ibuprofen, binder, filler, and disintegrant 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 ibuprofen, filler and disintegrant 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 certain concentration of binder aqueous solution is added, and granules are obtained by stirring and shearing.

[0036] The adhesive is hydroxypropyl methylcellulose, and the concentration of hydroxypropyl methylcellulose 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 prescription amount of ibuprofen, filler, disintegrant and binder for drug-loaded granules and mix them evenly in a hot melt granulator;

[0039] (2) Heat the uniformly mixed solid powder to 60±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 ibuprofen 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 ibuprofen granules of this invention require small amounts of excipients, have a simple preparation process, and are low in cost, resulting in considerable economic and social benefits.

[0046] Instruction manual illustrations

[0047] Figure 1 The dissolution curves of drug-loaded particles from Examples 8-12 are shown in the figures for 1-5 minutes. Detailed Implementation

[0048] Example 1: Screening of binders in drug-loaded particles

[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 60°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 basket method, with 900 ml of pH 6.8 phosphate buffer as the dissolution medium at a temperature of 37°C and a rotation speed of 100 rpm. Samples were taken at 1, 2, 3, 4, and 5 minutes. The dissolution solution was filtered, and 4 ml of the initial filtrate was discarded. 2 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 low melting point adhesives

[0058]

[0059] Table 2 Screening of Low Melting Point Adhesive Combinations

[0060]

[0061]

[0062] As can be seen from Table 1, the amount of fine powder obtained by using cetyl alcohol or polyethylene glycol 4000 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.

[0063] To obtain lower fine powder content and shorter dissolution time, we investigated the effects of low melting point binders on fine powder content, dissolution time and 5-minute dissolution rate under combined conditions. The results are shown in Table 2.

[0064] As can be seen from Table 2, under various combination conditions, the combination of hexadecyl alcohol and polyethylene glycol 4000 in a 1:1 ratio produces the lowest amount of fine powder and the shortest dissolution time. Although the dissolution rate is less than 95% at 5 min, it basically meets the dissolution standard. Other combinations differ from this combination in various evaluation indicators.

[0065] Since cetyl alcohol and polyethylene glycol 4000 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.

[0066] The ratio between hexadecyl alcohol and polyethylene glycol 4000 was changed, and the results are shown in Table 3.

[0067] Table 3 Screening of cetyl alcohol to polyethylene glycol 4000 ratio

[0068]

[0069] As shown in Table 3, when cetyl alcohol and polyethylene glycol 4000 are mixed in a mass ratio of 1:4 to 4:1, the dissolution time is less than 30 seconds, and the dissolution rate is greater than 90% within 5 minutes, but there are significant differences in particle size. When the ratio is 2:1 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 at a ratio of 3:1, there is the least fine powder, and the dissolution time is significantly shorter than that of drug-loaded particles prepared using cetyl alcohol or polyethylene glycol 4000 alone, with near-complete dissolution within 5 minutes. Therefore, the optimal ratio for mixing cetyl alcohol and polyethylene glycol 4000 is 3:1.

[0070] Example 2: Screening of the amount of low-melting-point binder in drug-loaded particles

[0071] Using hexadecyl alcohol, polyethylene glycol 4000, octadecyl alcohol, and a mixture of hexadecyl alcohol and polyethylene glycol 4000 as a low-melting-point binder

[0072] prescription

[0073]

[0074] The preparation method is as follows:

[0075] (1) Mix the weighed raw and auxiliary materials thoroughly to ensure that the low-melting-point adhesive is mixed evenly;

[0076] (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;

[0077] (3) The hot melt particles obtained in step (2) are granulated by an online granulation device to obtain the final product.

[0078] Table 4 Screening of Cetyl alcohol dosage

[0079]

[0080] As shown in Table 4, when the cetyl alcohol dosage is 4-16%, 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 10-12%, 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% in water within 5 minutes. However, when the cetyl alcohol dosage is increased or decreased, the amount of fine powder increases, and the uniformity of the particles decreases.

[0081] Therefore, when the amount of cetyl alcohol is 10-12%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0082] Table 5 Screening of Polyethylene Glycol 4000 Dosage

[0083]

[0084] As shown in Table 5, when the dosage of polyethylene glycol 4000 is 4-16%, the proportion of fine powder is less than 5.5%, the dissolution time is less than 30 seconds, and the solubility in water is above 95%. When the dosage is 4-8%, the proportion of fine powder is less than 5%, the dissolution time is less than 30 seconds, and the solubility in water is above 95%.

[0085] Therefore, when the amount of polyethylene glycol 4000 is 4-8%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0086] Table 6 Screening of Octadecyl Alcohol Dosage

[0087]

[0088] As shown in Table 6, when the dosage of octadecyl alcohol is 4-16%, the proportion of fine powder is less than 6.5%, the dissolution time is less than 30 seconds, and the dissolution rate is greater than 90%. When the dosage of octadecyl alcohol is 12%, the proportion of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter at 27 seconds, with a dissolution rate of 97% in water after 5 minutes.

[0089] Therefore, when the amount of octadecanol is 12-16%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0090] Table 7 Screening of total dosage when the ratio of hexadecyl alcohol to polyethylene glycol 4000 is 3:1

[0091]

[0092] As can be seen from Table 7, when the ratio of hexadecyl alcohol to polyethylene glycol 4000 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 18s, with a 5-minute dissolution rate of 98%. 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.

[0093] Therefore, when the ratio of hexadecyl alcohol to polyethylene glycol 4000 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.

[0094] From Tables 4-7, it can be concluded that when the low melting point binder content is 4-16%, the fine powder particle size, dissolution time, and 5-minute dissolution rate are all good. When hexadecyl alcohol, polyethylene glycol 4000, and octadecyl alcohol are used as low melting point binders individually, the preferred dosages of each component are: hexadecyl alcohol 10-12%, polyethylene glycol 4000 4-8%, and octadecyl alcohol 12-16%. When hexadecyl alcohol and polyethylene glycol 4000 are mixed in a 3:1 ratio as a low melting point binder, the preferred dosage is 8-12%.

[0095] Example 3: Screening of the mass ratio of ibuprofen:disintegrant:binder in drug-loaded particles

[0096] Using sodium carboxymethyl starch as a disintegrant and cetyl alcohol:polyethylene glycol 4000 at a ratio of 3:1 as a binder, the effects of different mass ratios of ibuprofen:disintegrant:binder on the particle size, dissolution time, and dissolution rate of drug-loaded particles were investigated.

[0097] Table 8 Screening of the proportions of main components, disintegrants, and binders

[0098]

[0099] As shown in Table 8, when cetyl alcohol and polyethylene glycol 4000 are mixed in a 3:1 ratio as a binder, the dissolution time does not exceed 30 seconds for different mass ratios of ibuprofen:disintegrant:binder within the range of 80–90:0–10:5–20, and the dissolution rate is not less than 90% within 5 minutes, but the particle size varies considerably. However, when the ratio is 80–90:0–10:10–15, not only is the particle size better and the fine powder less, but the dissolution rate is also not less than 95% within 5 minutes. When the ratio of ibuprofen:disintegrant:binder is 80:5–10:10–15, the fine powder is the least.

[0100] Example 4: Selection of filler type in drug-loaded particles

[0101] Using sodium carboxymethyl starch as a disintegrant and cetyl alcohol 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.

[0102] prescription

[0103]

[0104] Table 9. Screening of Filler Types

[0105]

[0106] As can be seen from Table 9, the amount of fine powder produced by using sucrose or mannitol 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.

[0107] When using a combination of sucrose and mannitol as a filler, changing the ratio of sucrose to mannitol surprisingly resulted in less fine powder and a shorter dissolution time, with better drug-loaded particles dissolving in 5 minutes. The results are shown in Table 10.

[0108] Table 10 Screening of sucrose to mannitol ratio

[0109]

[0110] As shown in Table 10, when sucrose and mannitol are mixed in a mass ratio of 1:4 to 4:1, the dissolution time is less than 30 seconds, the particle size is similar, and although the dissolution rate is greater than 90% at 5 minutes, there are significant differences. However, when the ratio is 1:1 to 2:1, 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% at 5 minutes. Especially at a ratio of 2:1, the amount of fine powder is the least, and the dissolution is the most complete.

[0111] Example 5: Screening of filler dosage

[0112]

[0113] Table 11 Screening of Sucrose Dosage

[0114]

[0115] As can be seen from Table 11, when the amount of sucrose is 22%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 25s. The dissolution rate in water at 5min is 98%, 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 in water at 5min is not significantly different, but both are less than the dissolution rate when the amount of sucrose is 22%.

[0116] Therefore, when the sucrose content is 22-26%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0117] Table 12 Screening of Mannitol Dosage

[0118]

[0119] As can be seen from Table 12, when the amount of mannitol is 18%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 22s. The dissolution rate at 5min is 97%, 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 much different, but both are less than the dissolution rate when the amount of mannitol is 18%.

[0120] Therefore, when the amount of mannitol is 18-22%, a drug-loaded particle with good particle size, dissolution time and dissolution rate can be obtained.

[0121] Table 13 Screening of lactose dosage

[0122]

[0123] As can be seen from Table 13, when the amount of lactose is 24-26%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, all not exceeding 25 seconds. The dissolution rate at 5 minutes 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 5 minutes does not differ much.

[0124] Therefore, when the lactose content is 24-26%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0125] Table 14 Screening of dosage when the sucrose to mannitol ratio is 2:1

[0126]

[0127] As can be seen from Table 14, when the ratio of sucrose to mannitol is fixed at 2:1 and the total amount of filler is 22%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter at 22s. The dissolution rate at 5min is 99%, which is greater than 95%. However, when the total amount of both is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min is greater than 90%.

[0128] When the ratio of sucrose to mannitol is fixed at 2:1, the particle size, dissolution time, and dissolution rate of the drug-loaded particles are optimal when the total amount of both is 22-26%.

[0129] Example 6: Screening of disintegrant types:

[0130] Using sucrose powder as a filler and polyethylene glycol 4000 as a binder, the effects of different disintegrants on the particle size, dissolution time, and dissolution rate of drug-loaded particles were investigated.

[0131]

[0132] Table 15 Screening of Disintegrant Types

[0133]

[0134] Table 16 Different ratios of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch as disintegrants

[0135]

[0136] As can be seen from Table 15, the amount of fine powder produced by using low-substituted hydroxypropyl cellulose or sodium carboxymethyl starch 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.

[0137] As shown in Table 16, when low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are mixed in different proportions, the dissolution time is less than 30 seconds when the mass ratio is 1:4-4:1, the particle size is similar, and the dissolution rate at 5 minutes is greater than 90%, but there are significant differences. However, when the ratio is 1:1-2:1, not only is the particle size better and the fine powder less, but the dissolution rate at 5 minutes is also greater than 95%. Especially when the ratio is 2:1, the amount of fine powder, dissolution time, and dissolution rate at 5 minutes are all optimal.

[0138] Example 7 Screening of disintegrant dosage

[0139]

[0140] Table 17 Screening of Total Sodium Carboxymethyl Starch Usage

[0141]

[0142] As can be seen from Table 17, when the amount of sodium carboxymethyl starch is 5-7%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 18s and 21s respectively, with a dissolution rate of more than 95% at 5min. However, when the amount of sodium carboxymethyl starch 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 is less than that when the amount of sodium carboxymethyl starch is 5-7%.

[0143] Therefore, when the amount of sodium carboxymethyl starch is 5-7%, a drug-loaded particle with good particle size, dissolution time and dissolution rate can be obtained.

[0144] Table 18 Screening of Total Amount of Low-Substituted Hydroxypropyl Cellulose

[0145]

[0146] As can be seen from Table 18, when the amount of low-substituted hydroxypropyl cellulose is 5%, the amount of fine powder is the lowest, the particles are more uniform, and the dissolution time is shorter, at 27s. The dissolution rate at 5min is 96%, which is greater than 95%. However, when the amount of low-substituted hydroxypropyl cellulose is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min in water is not significantly different, but both are less than the dissolution rate when the amount of low-substituted hydroxypropyl cellulose is 5%.

[0147] Therefore, when the amount of low-substituted hydroxypropyl cellulose is 5%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0148] Table 19 Screening of total dosage when the ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 2:1

[0149]

[0150] As can be seen from Table 19, when the ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is fixed at 2:1, and the total amount of disintegrant is 7%, 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 97%, which is greater than 95%. However, when the total amount of both is increased or decreased, the amount of fine powder increases, the uniformity of particles decreases, and the dissolution rate at 5min is greater than 90%, but less than the dissolution rate when the total amount is 5%.

[0151] Therefore, when the ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is fixed at 2:1 and the total amount of both is 7-9%, a drug-loaded particle with better particle size, dissolution time and dissolution rate can be obtained.

[0152] Based on Tables 17-19, it can be concluded that when using a single disintegrant, adding 5% of low-substituted hydroxypropyl cellulose, adding 5-7% of sodium carboxymethyl starch, or adding 7-9% of a mixture of the two in a 2:1 ratio can all achieve better particle size, dissolution time, and dissolution rate.

[0153] Example 8: Preparation of drug-loaded particles

[0154] prescription:

[0155]

[0156] The preparation method is the same as in Example 1.

[0157] Example 9: Preparation of drug-loaded particles

[0158] prescription:

[0159]

[0160] The preparation method is the same as in Example 1.

[0161] Example 10 Preparation of drug-loaded particles

[0162] prescription:

[0163]

[0164] The preparation method is the same as in Example 1.

[0165] Example 11 Preparation of drug-loaded particles

[0166] prescription:

[0167]

[0168] The preparation method is the same as in Example 1.

[0169] Example 12 Preparation of drug-loaded particles

[0170] prescription:

[0171]

[0172] Example 13 Properties of drug-loaded particles from Examples 8-12

[0173] Table 20 Properties of Drug-Loaded Particles in Examples 8-12

[0174]

[0175] Table 21 Dissolution results of drug-loaded particles in Examples 8-12 at 1-5 min

[0176]

[0177] Example 14: Screening of Flavoring Granular Fillers:

[0178]

[0179] The preparation method is as follows:

[0180] (1) Weigh out the prescribed amounts of filler, sweetener, acidulant and flavoring and mix them evenly;

[0181] (2) Add an appropriate amount of adhesive to the mixture obtained in step (1), cut and granulate, and sieve to prepare flavored granules.

[0182] Table 22 Screening of Flavored Granular Fillers

[0183]

[0184] The results showed that the addition of various fillers improved the patient's comfort level, while sucrose provided the best comfort level when used as a filler.

[0185] Example 15: Screening of types of flavoring granules, sweeteners, and acidulants:

[0186]

[0187] Table 23 Screening of flavoring granules for sweeteners and acidulants

[0188]

[0189]

[0190] Adding different acidulants and sweeteners can improve the overall comfort of patients, with neotame as the sweetener and citric acid as the acidulant providing the best overall comfort.

Claims

1. An anhydrous ibuprofen granule, comprising drug-loaded granules and flavoring granules, characterized in that, The drug-loaded particles comprise the following components: ibuprofen, filler, disintegrant, and binder. The weight percentage of each component in the drug-loaded particles is as follows: ibuprofen 65.0–70.0%, disintegrant 2.0–8.0%, binder 4.0%–16.0%, with the remainder being filler. The binder is a mixture of hexadecyl alcohol and polyethylene glycol 4000, with a mass ratio of hexadecyl alcohol to polyethylene glycol 4000 of 2:1 to 3:

1. The filler is a mixture of sucrose and mannitol, with a mass ratio of sucrose to mannitol of 1:1 to 2:

1. The disintegrant is a mixture of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch, with a mass ratio of low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch of 2:

1.

2. The ibuprofen anhydrous granules according to claim 1, characterized in that, The mass ratio of ibuprofen: disintegrant: binder is 80: 5-10: 10-15.

3. The ibuprofen anhydrous granules according to claim 1 or 2, characterized in that, The flavoring granules contain the following components: filler, sweetener, acidulant and flavoring, with the following weight percentages: filler 88.0% to 99.7%, sweetener 0.1% to 8.0%, acidulant 0.1% to 3.0%, and flavoring 0.1% to 1.0%.

4. The ibuprofen anhydrous granules according to claim 3, characterized in that, The filler is selected from one or more of sucrose, lactose, mannitol, sorbitol, microcrystalline cellulose, and maltitol; the sweetener is selected from one or more of stevia, sucralose, mannitol, lactitol, erythritol, aspartame, sucrose, sorbitol, neotame, and glycyrrhizin; the acidulant is selected from one or more of citric acid, lactic acid, malic acid, tartaric acid, and fumaric acid; and 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.

5. The method for preparing anhydrous ibuprofen granules according to claim 1, characterized in that, Includes the following steps: (1) Preparation of drug-loaded particles: Ibuprofen, binder, filler, and disintegrant 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.

6. The use of the ibuprofen anhydrous granules according to any one of claims 1-4 in the preparation of a medicament for treating pain.

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