Arginine ibuprofen biphasic sustained release preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an arginine ibuprofen biphasic sustained release preparation and a preparation method thereof. Through a two-phase system of quick-release particles and slow-release particles, the problems that a traditional preparation takes effect slowly, is short in medicine effect and poor in taste are solved. Wherein the quick-release granules are prepared by mixing and granulating ibuprofen arginine, a filling agent, an adhesive and a natural flavoring agent, so that the effective blood concentration can be ensured to be reached within 15 minutes after the medicine is orally taken so as to quickly relieve pain, and the bad flavor of the medicine can be synchronously covered; the sustained-release granules are based on an ibuprofen arginine drug-loading core, the outer layer of the sustained-release granules is coated with a sustained-release film formed by a sustained-release agent and a plasticizer, and the effective blood concentration can be stably maintained for 6-8 hours, so that the medicine taking frequency is reduced, the sustained-release granules only need to be taken for 1-2 times every day, the medication compliance of a patient is greatly improved, and the sustained-release granules are suitable for clinical application. The traditional Chinese medicine composition is especially suitable for clinical scenes needing long-term or repeated analgesia such as chronic arthritis and postoperative pain, has excellent safety and practicability, and has a wide market application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to an arginine ibuprofen biphasic sustained-release formulation and its preparation method. Background Technology

[0002] Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), possesses significant antipyretic, analgesic, and anti-inflammatory effects, and is widely used to relieve mild to moderate pain and treat various acute and chronic arthritis, soft tissue rheumatic pain, and other conditions, holding an important position in clinical medication. However, ibuprofen itself has poor water solubility, which to some extent affects the drug's absorption rate, resulting in a relatively slow onset of action after oral administration and difficulty in quickly relieving patients' acute pain symptoms. To address this issue, the Italian company Zambon SPA developed arginine ibuprofen. Arginine, a basic amino acid, significantly improves the water solubility of ibuprofen after binding with it, allowing the drug to dissolve more quickly in the gastrointestinal tract and be absorbed into the bloodstream after oral administration, thereby effectively shortening the onset time and meeting the clinical need for rapid relief of acute pain. Currently, arginine ibuprofen has become one of the commonly used drugs for treating acute pain in clinical practice, and related tablets, capsules, and other conventional dosage forms have also been put into market use.

[0003] However, existing commercially available conventional formulations of arginine ibuprofen have significant limitations in terms of duration of action. Due to the lack of an effective sustained-release design in these formulations, the drug is rapidly absorbed and reaches peak plasma concentration after entering the body, followed by a rapid decline in plasma concentration due to rapid metabolism and excretion. This process results in a short duration of effective plasma concentration, typically only 4–6 hours. To maintain sustained analgesic and anti-inflammatory effects, patients need to repeat the medication at short dosing intervals (e.g., every 4–6 hours), which not only increases the burden of patient adherence but also increases the risk of large fluctuations in plasma concentration due to missed doses or irregular dosing, potentially leading to unstable efficacy or an increased risk of adverse reactions.

[0004] Meanwhile, in clinical settings, different patients have varying degrees of disease severity and pain relief needs. For patients experiencing acute pain attacks, medication needs to act rapidly to quickly control the pain; however, after initial pain relief, medication needs to release slowly and continuously to maintain a stable and effective blood drug concentration, achieving long-term treatment and reducing the frequency of dosing. Existing conventional formulations cannot simultaneously meet the dual clinical needs of rapid onset of action and long-term sustained release.

[0005] Therefore, developing an arginine ibuprofen formulation that can achieve rapid onset of action, long-lasting sustained release, and has a stable preparation process and controllable quality has significant clinical application value and market prospects. Summary of the Invention

[0006] To address the problems of short duration of action, inability to simultaneously meet the clinical needs of rapid onset and long-lasting release, and poor patient compliance in existing arginine ibuprofen formulations, this invention provides a biphasic sustained-release formulation of arginine ibuprofen and its preparation method.

[0007] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0008] An arginine ibuprofen biphasic sustained-release formulation comprising immediate-release granules and sustained-release granules;

[0009] The immediate-release granules contain arginine ibuprofen, fillers, binders, and natural flavoring agents;

[0010] The sustained-release particles contain an arginine ibuprofen drug-carrying core, a sustained-release agent, and a plasticizer;

[0011] The arginine ibuprofen drug-carrying core comprises arginine ibuprofen, a filler, and a binder;

[0012] The sustained-release agent comprises ethyl cellulose and hydroxypropyl methylcellulose; the plasticizer is triethyl citrate.

[0013] Based on the mass of arginine ibuprofen core, the mass percentage of the sustained-release agent is 15% to 35%.

[0014] Compared to existing technologies, the arginine ibuprofen biphasic sustained-release formulation provided by this invention consists of immediate-release granules and sustained-release granules. In terms of drug release, the immediate-release granules achieve rapid onset of action, reaching an effective blood concentration within 15 minutes after oral administration, quickly relieving acute pain and solving the problems of slow onset and inability to handle sudden pain in traditional sustained-release formulations. The sustained-release granules, based on an arginine ibuprofen drug-carrying core, are coated with a sustained-release agent composed of ethyl cellulose and hydroxypropyl methylcellulose, and a triethyl citrate plasticizer. By controlling the content of the sustained-release agent, an effective blood concentration is maintained for 6-8 hours, avoiding the shortcomings of short-acting and frequent dosing required by ordinary formulations. Through the synergistic effect of the immediate-release and sustained-release granules, the dual clinical needs of rapid onset of action and long-term sustained release can be met, making it particularly suitable for chronic arthritis and postoperative pain requiring long-term pain control.

[0015] In terms of convenience and adherence, compared to ordinary arginine ibuprofen preparations (which require 4-5 doses per day), the arginine ibuprofen biphasic sustained-release preparation provided by this invention only requires 1-2 doses per day, significantly reducing the frequency of medication and lowering the risk of missed doses. This is especially beneficial for elderly patients with poor memory or children with low compliance with medication, as it can significantly improve medication adherence and further ensure the stability of treatment effects.

[0016] Furthermore, the mass ratio of the immediate-release granules to the sustained-release granules is (40-70):(60-30).

[0017] The optimal mass ratio of immediate-release granules to sustained-release granules achieves a balance between rapid onset of action and long-lasting sustained release: on the one hand, immediate-release granules ensure rapid onset of action after oral administration, promptly relieving acute pain; on the other hand, after the immediate-release granules take effect, the sustained-release granules' continuous release characteristics stably maintain a long-lasting effect for 6-8 hours. This avoids the problem of interrupted efficacy due to insufficient release from sustained-release granules, and also prevents treatment delays caused by excessively slow initial release from sustained-release granules. Ultimately, a stable drug release curve is formed, significantly reducing the fluctuation range of blood drug concentration in the body and ensuring the stability and safety of the medication effect.

[0018] Furthermore, based on the mass of the arginine ibuprofen drug-carrying core as 100%, the mass percentage of the plasticizer is 1.5% to 3.5%.

[0019] The optimal amount of plasticizer helps ensure that the sustained-release membrane can stably perform its function of controlling the slow release of drugs.

[0020] Furthermore, the mass ratio of arginine ibuprofen, filler, and binder in the arginine ibuprofen drug-loaded core is 3:(1-10):(0.03-0.1).

[0021] Furthermore, the mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose in the sustained-release agent is 2:1 to 4:1.

[0022] The sustained-release membrane formed by the optimal mass ratio of ethyl cellulose and hydroxypropyl methylcellulose combines barrier and permeability, ensuring uniform drug release and avoiding excessively rapid or slow release, thus facilitating the stable efficacy of arginine ibuprofen.

[0023] Furthermore, the filler and binder in the arginine ibuprofen drug-carrying core are selected from the same types as the filler and binder in the immediate-release granules; wherein the filler is sorbitol and the binder is hydroxypropyl methylcellulose.

[0024] Using the same excipients for the drug-loaded core and the immediate-release granules can avoid fluctuations in formulation quality caused by compatibility issues between different excipients and ensure that the drug release curves of different batches of formulations are consistent.

[0025] Sorbitol was selected as the filler and hydroxypropyl methylpropionate as the binder in both immediate-release and sustained-release granules. This not only improves the solubility of ibuprofen and arginine, ensuring rapid disintegration of the immediate-release granules after oral administration, allowing the drug to reach an effective blood concentration in a short time, but also facilitates the uniform dispersion of ibuprofen and arginine in the drug-loaded core. This lays the foundation for the formation of a uniform and controllable sustained-release film in the subsequent sustained-release coating, avoiding drug release fluctuations caused by uneven drug distribution.

[0026] Furthermore, the natural flavoring agent is glycyrrhizin and steviol glycoside in a mass ratio of 1:(0.5-2).

[0027] Arginine ibuprofen itself has a slightly bitter and irritating odor, which can easily cause taste discomfort in patients (especially children and elderly patients) when taken orally. By combining it with two natural flavoring agents, glycyrrhizin and steviol glycoside, the bitterness and irritating odor can be effectively masked, improving patient compliance, especially for children with more sensitive taste buds.

[0028] Furthermore, the immediate-release granules comprise: 3 parts arginine ibuprofen, 1 to 10 parts filler, 0.03 to 0.1 parts binder, and 0.1 to 0.2 parts natural flavoring agent.

[0029] This invention also provides a method for preparing a biphasic sustained-release formulation of arginine ibuprofen, comprising the following steps:

[0030] S1, Preparation of immediate-release granules: Arginine ibuprofen, filler and natural flavoring agent are mixed evenly, binder solution is added to form a soft mass, sieved and granulated, dried to obtain immediate-release granules;

[0031] S2, Preparation of sustained-release granules: Arginine ibuprofen and filler are mixed evenly, binder solution is added to form soft material, granulated by sieve, and dried to obtain arginine ibuprofen drug-loaded core;

[0032] Add the sustained-release agent and plasticizer to purified water, mix well, and obtain a sustained-release coating solution;

[0033] The sustained-release coating solution was used to coat the arginine ibuprofen drug-carrying core to obtain sustained-release particles;

[0034] S3, mix the immediate-release granules and the sustained-release granules evenly to obtain an arginine ibuprofen biphasic sustained-release formulation.

[0035] The present invention provides a method for preparing a dual-phase sustained-release formulation of arginine ibuprofen. In the preparation of immediate-release granules, arginine ibuprofen is directly mixed with fillers and natural flavoring agents for granulation. This not only improves the solubility and uniform dispersibility of arginine ibuprofen through the fillers, but also ensures that the natural flavoring agents are uniformly dispersed within the granules, simultaneously masking unpleasant flavors during oral administration. In the preparation of sustained-release granules, arginine ibuprofen, fillers, and binders are used to form a drug-loaded core, ensuring uniform dispersion of arginine ibuprofen within the core and forming granules of uniform size. This provides a smooth and uniform carrier for subsequent sustained-release coating, preventing uneven coating thickness due to uneven core surface, which could lead to either burst release or excessively slow release. Furthermore, the process of preparing immediate-release and sustained-release granules separately before mixing further ensures the stable performance of the dual-phase drug release function, guarantees medication stability, and achieves the dual objectives of rapid onset and long-lasting sustained release.

[0036] Furthermore, in S1, the mass concentration of the adhesive solution is 2% to 5%.

[0037] Furthermore, in S1, the granulation process involves passing the material through a 20-mesh sieve.

[0038] Furthermore, in S2, the mass concentration of the adhesive solution is 2% to 5%.

[0039] Furthermore, in S2, the solid content of the sustained-release coating solution is 10% to 20%.

[0040] Furthermore, in S2, the granulation process involves passing the material through a 24-mesh sieve.

[0041] Furthermore, in both S1 and S2, the drying temperature is 50°C to 60°C.

[0042] Furthermore, in S2, the coating is applied by bottom spraying in a fluidized bed, with an inlet air temperature of 40℃~50℃ and a material temperature of 35℃~42℃.

[0043] Specifically, the arginine ibuprofen biphasic sustained-release formulation is in granule form.

[0044] The arginine ibuprofen biphasic sustained-release formulation provided by this invention solves the problems of slow onset, short duration of action, and poor taste of traditional formulations through a biphasic system of immediate-release granules and sustained-release granules. The immediate-release granules are granulated by mixing arginine ibuprofen, fillers, binders, and natural flavoring agents, ensuring that the drug reaches an effective blood concentration within 15 minutes after oral administration to quickly relieve pain, while simultaneously masking the drug's unpleasant flavor. The sustained-release granules, based on an arginine ibuprofen drug-carrying core, are coated with a sustained-release film formed by a sustained-release agent and plasticizer, which can stably maintain an effective blood concentration for 6-8 hours, thereby reducing the frequency of dosing to only 1-2 times daily, significantly improving patient compliance. It is particularly suitable for clinical scenarios requiring long-term or repeated analgesia, such as chronic arthritis and postoperative pain, and possesses excellent safety and practicality, with broad market application prospects. Attached Figure Description

[0045] Figure 1 The blood concentration-time curves are for the arginine ibuprofen biphasic sustained-release granules prepared in Example 1 and the commercially available product. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0047] To better illustrate the present invention, further examples are provided below.

[0048] Example 1

[0049] This embodiment provides an arginine ibuprofen biphasic sustained-release granule formulation, with the following specific formula (500 sachets):

[0050] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0051] Composition of sustained-release granules: 1074.3g arginine ibuprofen drug-carrying core, 195.3g sustained-release agent, and 19.53g triethyl citrate;

[0052] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core drug delivery system for arginine ibuprofen includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 3:1.

[0053] The preparation method of the above-mentioned arginine ibuprofen biphasic sustained-release granules is as follows:

[0054] S1, Preparation of immediate-release granules:

[0055] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0056] The weighed arginine ibuprofen, sorbitol, glycyrrhizin and steviol glycosides were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 50-60℃ to obtain immediate-release granules.

[0057] S2, Preparation of sustained-release granules:

[0058] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0059] The weighed arginine ibuprofen and sorbitol were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 24-mesh sieve and dried at 55°C to obtain the arginine ibuprofen drug-loaded core.

[0060] Ethyl cellulose, hydroxypropyl methyl cellulose and triethyl citrate are added to purified water to prepare a sustained-release coating solution with a solid content of 10-20%.

[0061] The slow-release coating solution is used for coating via a fluidized bed bottom spray process, with an inlet air temperature of 45°C and a material temperature of 38°C, to obtain slow-release granules.

[0062] S3, the immediate-release granules and the sustained-release granules are mixed evenly at a mass ratio of 50:50, and packaged into arginine ibuprofen biphasic sustained-release granules containing 0.8g of arginine ibuprofen (calculated as ibuprofen) per granule.

[0063] Example 2

[0064] This embodiment provides an arginine ibuprofen biphasic sustained-release granule formulation, the specific formulation of which is as follows:

[0065] Immediate-release granules composition: arginine ibuprofen 368.9g, sorbitol 123g, hydroxypropyl methylcellulose 7.8g, natural flavoring agent 12.3g;

[0066] Composition of sustained-release granules: 499.7g arginine ibuprofen drug-carrying core, 174.9g sustained-release agent, and 17.49g triethyl citrate;

[0067] The natural flavoring agents are glycyrrhizin and steviol glycosides in a 1:1 mass ratio; the core of the arginine ibuprofen drug delivery system includes: 368.9g of arginine ibuprofen + 123g of sorbitol + 7.8g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a 4:1 mass ratio.

[0068] The preparation method of the above-mentioned arginine ibuprofen biphasic sustained-release granules is as follows:

[0069] S1, Preparation of immediate-release granules:

[0070] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0071] The weighed arginine ibuprofen, sorbitol, glycyrrhizin and steviol glycosides were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 50-60℃ to obtain immediate-release granules.

[0072] S2, Preparation of sustained-release granules:

[0073] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0074] The weighed arginine ibuprofen and sorbitol were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 24-mesh sieve and dried at 60°C to obtain the arginine ibuprofen drug-loaded core.

[0075] Ethyl cellulose, hydroxypropyl methyl cellulose and triethyl citrate are added to purified water to prepare a sustained-release coating solution with a solid content of 10-20%.

[0076] The slow-release coating solution is used for coating via a fluidized bed bottom spray process, with an inlet air temperature of 40°C and a material temperature of 35°C, to obtain slow-release granules.

[0077] S3, the immediate-release granules and the sustained-release granules are mixed evenly at a mass ratio of 70:30, and packaged into arginine ibuprofen biphasic sustained-release granules containing 0.8g of arginine ibuprofen (calculated as ibuprofen) per granule.

[0078] Example 3

[0079] This embodiment provides an arginine ibuprofen biphasic sustained-release granule formulation, the specific formulation of which is as follows:

[0080] The composition of the immediate-release granules is: arginine ibuprofen 368.9g, sorbitol 1230g, hydroxypropyl methylcellulose 12.3g, and natural flavoring agent 24.6g.

[0081] Composition of sustained-release granules: 1611.2g arginine ibuprofen drug-carrying core, 242.6g sustained-release agent, and 24.26g triethyl citrate;

[0082] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:2; the core drug delivery system for arginine ibuprofen includes: 368.9g of arginine ibuprofen + 1230g of sorbitol + 12.3g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 2:1.

[0083] The preparation method of the above-mentioned arginine ibuprofen biphasic sustained-release granules is as follows:

[0084] S1, Preparation of immediate-release granules:

[0085] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0086] The weighed arginine ibuprofen, sorbitol, glycyrrhizin and steviol glycosides were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 20-mesh sieve and dried at 50-60℃ to obtain immediate-release granules.

[0087] S2, Preparation of sustained-release granules:

[0088] Weigh each component according to the formula, dissolve hydroxypropyl methylcellulose in purified water to obtain a hydroxypropyl methylcellulose aqueous solution with a mass concentration of 2-5%.

[0089] The weighed arginine ibuprofen and sorbitol were mixed evenly, and hydroxypropyl methylcellulose aqueous solution was added to make a soft mass. The mass was granulated by passing it through a 24-mesh sieve and dried at 50°C to obtain the arginine ibuprofen drug-loaded core.

[0090] Ethyl cellulose, hydroxypropyl methyl cellulose and triethyl citrate are added to purified water to prepare a sustained-release coating solution with a solid content of 10-20%.

[0091] The slow-release coating solution is used for coating via a fluidized bed bottom spray process, with an inlet air temperature of 50°C and a material temperature of 42°C, to obtain slow-release granules.

[0092] S3, the immediate-release granules and the sustained-release granules are mixed evenly at a mass ratio of 40:60, and packaged into arginine ibuprofen biphasic sustained-release granules containing 0.8g of arginine ibuprofen (calculated as ibuprofen) per granule.

[0093] Comparative Example 1

[0094] This comparative example provides a biphasic sustained-release granule formulation of arginine ibuprofen, which differs from Example 1 only in that the amount of sustained-release agent and plasticizer added is reduced. The specific formulation is as follows:

[0095] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0096] Composition of sustained-release granules: 1074.3g arginine ibuprofen drug-carrying core, 97.7g sustained-release agent, and 9.77g triethyl citrate;

[0097] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core drug delivery system for arginine ibuprofen includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 3:1.

[0098] Arginine ibuprofen biphasic sustained-release granules were prepared using the same method as in Example 1, which will not be repeated here.

[0099] Comparative Example 2

[0100] This comparative example provides a biphasic sustained-release granule formulation of arginine ibuprofen, which differs from Example 1 only in that the amount of sustained-release agent and plasticizer added is increased. The specific formulation is as follows:

[0101] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0102] Composition of sustained-release granules: 1074.3g arginine ibuprofen drug-carrying core, 390.7g sustained-release agent, and 39.07g triethyl citrate;

[0103] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core drug delivery system for arginine ibuprofen includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 3:1.

[0104] Arginine ibuprofen biphasic sustained-release granules were prepared using the same method as in Example 1, which will not be repeated here.

[0105] Comparative Example 3

[0106] This comparative example provides a biphasic sustained-release granule formulation of arginine ibuprofen, which differs from Example 1 only in that the plasticizer is replaced with PEG 6000. The specific formulation is as follows:

[0107] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0108] Composition of sustained-release granules: 1074.3g arginine ibuprofen drug-loaded core, 195.3g sustained-release agent, 19.53g PEG 6000;

[0109] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core drug delivery system for arginine ibuprofen includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose; and the sustained-release agents are ethyl cellulose and hydroxypropyl methylcellulose in a mass ratio of 3:1.

[0110] Arginine ibuprofen biphasic sustained-release granules were prepared using the same method as in Example 1, which will not be repeated here.

[0111] Comparative Example 4

[0112] This comparative example provides a biphasic sustained-release granule formulation of arginine ibuprofen, which differs from Example 1 only in that the sustained-release agent is replaced with a single hydroxypropyl methylcellulose. The specific formulation is as follows:

[0113] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0114] The sustained-release granules consist of: 1074.3g of arginine ibuprofen drug-loaded core, 195.3g of hydroxypropyl methylcellulose, and 19.53g of triethyl citrate.

[0115] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core of the arginine ibuprofen drug delivery system includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose.

[0116] Arginine ibuprofen biphasic sustained-release granules were prepared using the same method as in Example 1, which will not be repeated here.

[0117] Comparative Example 5

[0118] This comparative example provides a biphasic sustained-release granule formulation of arginine ibuprofen, which differs from Example 1 only in that the sustained-release agent is replaced with a single ethyl cellulose. The specific formulation is as follows:

[0119] Composition of immediate-release granules: arginine ibuprofen 368.9g, sorbitol 700g, hydroxypropyl methylcellulose 5.4g, natural flavoring agent 20g;

[0120] The sustained-release granules consist of: 1074.3g of arginine ibuprofen drug-carrying core, 195.3g of ethyl cellulose, and 19.53g of triethyl citrate.

[0121] The natural flavoring agents are glycyrrhizin and steviol glycosides in a mass ratio of 1:0.6; the core of the arginine ibuprofen drug delivery system includes: 368.9g of arginine ibuprofen + 700g of sorbitol + 5.4g of hydroxypropyl methylcellulose.

[0122] Arginine ibuprofen biphasic sustained-release granules were prepared using the same method as in Example 1, which will not be repeated here.

[0123] Dissolution curve

[0124] Using the arginine ibuprofen biphasic sustained-release granules prepared in Example 1 as a reference, the dissolution curves of the arginine ibuprofen biphasic sustained-release granules prepared in Examples 1-3 and Comparative Examples 1-2 were tested using the second method (paddle method) of the dissolution determination method in the 2020 edition of the Chinese Pharmacopoeia. The test method is as follows, and the results are shown in Table 1.

[0125] Medium: 900 mL of pH 6.8 phosphate buffer

[0126] Speed: 50 rpm

[0127] Sampling points: 5 min, 15 min, 30 min, 60 min, 120 min, 240 min, 360 min

[0128] Table 1. Dissolution rates (%) of Examples 1-3 and Comparative Examples 1-2 at different sampling times.

[0129]

[0130] The results show that after increasing or decreasing the amount of sustained-release agent in Comparative Examples 1 and 2, the curves are not similar to those in Example 1, with similarity factors of 43.11 and 45.43, respectively. This indicates that the ratio of sustained-release agent dosages of ethyl cellulose and hydroxypropyl methylcellulose in this invention is the key to ensuring stable dissolution performance of the formulation and matching with the ideal drug release curve.

[0131] The dissolution curves of the immediate-release granules, sustained-release granules, and arginine ibuprofen biphasic sustained-release granules prepared in Example 1 were determined using the same method described above, and the results are shown in Table 2.

[0132] Table 2 Dissolution rates (%) of immediate-release granules, sustained-release granules, and biphasic sustained-release granules at different sampling times.

[0133] Time (min) Immediate-release granules Sustained-release granules Biphasic sustained-release granules 5 85.2±3.5 1±0.2 41.6±2.8 15 95.6±2.8 1±0.8 48.7±3.2 30 98.3±1.5 10.6±2.1 55.9±2.7 60 99.2±0.8 42.5±3.0 68.3±2.5 120 - 68.9±2.8 85.1±1.9 240 - 85.7±1.5 90.3±1.2 360 - 96.8±0.9 96.5±0.8

[0134] The results show that the biphasic sustained-release granules provided by this invention combine the advantages of immediate-release and sustained-release granules. The release rate at 5 minutes is 41.6±2.8%, and at 360 minutes it is 96.5±0.8%. The immediate-release granules achieve rapid drug release in the initial stage, while the sustained-release granules ensure the continuous release of the drug in the subsequent stage. This allows the formulation to maintain an effective drug concentration for a longer period of time, achieving the goals of biphasic sustained release, reducing the frequency of medication, and improving patient medication compliance. It is suitable for scenarios such as chronic pain that require long-term stable analgesia.

[0135] In vivo sustained release effect

[0136] A fasting drug administration experiment was conducted using 12 healthy beagles, half male and half female, weighing 2.5–3.5 kg. A comparative fasting drug administration experiment was carried out. Prior to the experiment, all beagles underwent a 7-day acclimatization period (environment: temperature 22–25℃, relative humidity 50%–60%, 12h light / 12h dark cycle, free access to water), and were fasted for 24 hours prior to the experiment (free access to water only) to eliminate interference from food on drug absorption.

[0137] Twelve beagle dogs were randomly divided into two groups of six each, with three males and three females. The control group was given commercially available arginine ibuprofen (trade name: Sibaide, batch number: 1006403, specification: each pack contains 0.4g of arginine ibuprofen (calculated as ibuprofen), dosage: 20mg / kg, dissolved in an appropriate amount of purified water and administered orally by gavage.

[0138] The experimental group was given the arginine ibuprofen biphasic sustained-release granules prepared in Example 1 of the present invention (specification: each granule contains 0.8g of arginine ibuprofen) at a dose of 40mg / kg, which was also dissolved in an appropriate amount of purified water and administered orally.

[0139] Blood samples of 3 mL were collected from veins at 0 h before medication and at 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 18 h, and 24 h after medication. The samples were placed in anticoagulant centrifuge tubes containing heparin sodium and centrifuged at 3000 rpm for 10 min to separate the plasma. The plasma samples were then stored in an ultra-low temperature freezer at -80℃ for later testing.

[0140] The concentration of ibuprofen in plasma was determined by high performance liquid chromatography (HPLC), under the following chromatographic conditions:

[0141] The chromatographic column was a C18 column (250 mm × 4.6 mm, 5 μm); the mobile phase was methanol-acetonitrile-water-phosphoric acid (55:10:35:0.03); the flow rate was 1.0 mL / min; the detection wavelength was 263 nm; the column temperature was 30 ℃; and the injection volume was 20 μL. The concentration of ibuprofen in plasma at each time point was calculated using the external standard method, and a plasma concentration-time curve was plotted. The results are shown below. Figure 1 As shown in Table 3.

[0142] Table 3

[0143]

[0144] The results show that Embodiment 1 of the present invention is similar to the commercially available product (Scbott) in T... max C max The high degree of similarity demonstrates that the time to peak concentration and C10 concentration of this invention in vivo are similar. maxAt the same level, the drug-time curves show that the arginine ibuprofen biphasic sustained-release granules prepared in this invention have a longer effective blood concentration maintenance time.

[0145] Taste evaluation

[0146] Thirty healthy volunteers were recruited (excluding those with abnormal taste sensitivity or drug allergies). A randomized, double-blind method was used to have the volunteers orally administer the biphasic sustained-release granules of this invention (Example 1), a commercially available arginine ibuprofen formulation (Sibide), and a comparative granule formulation without natural flavoring agents. Subjective evaluations were conducted based on bitterness masking, cooling sensation, aftertaste, and overall acceptability. The taste evaluation criteria are shown in Table 4, and the evaluation results are shown in Table 5.

[0147] The only difference between the comparative granules and those of Example 1 is the removal of the natural flavoring agent; otherwise, they are identical.

[0148] Table 4 Taste Evaluation Criteria

[0149]

[0150] Table 5 Subjective Evaluation Scores

[0151] Example 1 8.9±0.7 8.5±0.8 8.7±0.6 8.8±0.7 Commercially available product (Scbot 1006403) 7.2±1.1 6.8±1.2 6.5±1.3 6.9±1.0 Comparative example (without flavoring agents) 3.5±1.5 2.8±1.7 2.9±1.6 3.1±1.4

[0152] The results show that the bitterness masking score of Example 1 of this invention is 8.9±0.7, while that of the commercially available product (Sibaide 1006403) is 7.2±1.1, and that of the comparative example (without flavoring agent) is only 3.5±1.5. This indicates that the present invention is significantly more effective than the commercially available product in masking the bitterness of the drug, and far exceeds that of the comparative example without flavoring agent. This proves that the natural flavoring agent of glycyrrhizin-stevioside added in the present invention can effectively mask bitterness. The overall acceptability score of Example 1 of this invention is 8.8±0.7, while that of the commercially available product is 6.9±1.0, and that of the comparative example is only 3.1±1.4. Overall, the biphasic sustained-release granules prepared in Example 1 of this invention significantly improve the taste and acceptability of the formulation, and are especially suitable for children, the elderly and other taste-sensitive populations.

[0153] stability

[0154] Accelerated testing was conducted on Example 1 of the present invention and a commercially available product (Sibaide 1006403) under the following conditions: 40℃±2℃, RH 75%±5%, and the product was stored for 6 months. The product content, loss on drying, free ibuprofen, and related substances were investigated. The results are shown in Table 6.

[0155] Table 6 Stability Results

[0156]

[0157]

[0158] The results show that, under accelerated conditions, the content and free ibuprofen index of the granules of this invention did not change significantly, the increase in drying weight loss was less than 0.3%, and the increase in total impurities was less than 0.05%, which fully meets the requirements for pharmaceutical stability. Moreover, compared with commercially available products, the fluctuations of each key stability index are smaller and the stability is better, which effectively solves the problems of easy degradation and increased impurities in traditional preparations during long-term storage, and is conducive to further ensuring the safety of clinical medication.

[0159] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A biphasic sustained-release formulation of arginine ibuprofen, characterized in that, Includes immediate-release granules and sustained-release granules; The immediate-release granules contain arginine ibuprofen, fillers, binders, and natural flavoring agents; The sustained-release particles contain an arginine ibuprofen drug-carrying core, a sustained-release agent, and a plasticizer; The arginine ibuprofen drug-carrying core comprises arginine ibuprofen, a filler, and a binder; The sustained-release agent comprises ethyl cellulose and hydroxypropyl methylcellulose; the plasticizer is triethyl citrate. Based on the mass of arginine ibuprofen core, the mass percentage of the sustained-release agent is 15% to 35%.

2. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, The mass ratio of immediate-release granules to sustained-release granules is (40-70):(60-30).

3. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, Based on the mass of the arginine ibuprofen drug-carrying core as 100%, the mass percentage of the plasticizer is 1.5% to 3.5%.

4. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, The mass ratio of arginine ibuprofen, filler, and binder in the arginine ibuprofen drug-loaded core is 3:(1-10):(0.03-0.1).

5. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, The mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose in the sustained-release agent is 2:1 to 4:

1.

6. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, The filler and binder in the arginine ibuprofen drug-carrying core are selected from the same types as the filler and binder in the immediate-release granules; wherein the filler is sorbitol and the binder is hydroxypropyl methylcellulose.

7. The arginine ibuprofen biphasic sustained-release formulation as described in claim 1, characterized in that, The natural flavoring agent is glycyrrhizin and steviol glycoside in a mass ratio of 1:(0.5-2).

8. The arginine ibuprofen biphasic sustained-release formulation according to any one of claims 1 to 7, characterized in that, The immediate-release granules comprise: 3 parts arginine ibuprofen, 1 to 10 parts filler, 0.03 to 0.1 parts binder, and 0.1 to 0.2 parts natural flavoring agent.

9. A method for preparing the arginine ibuprofen biphasic sustained-release formulation according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1, Preparation of immediate-release granules: Arginine ibuprofen, filler and natural flavoring agent are mixed evenly, binder solution is added to form a soft mass, sieved and granulated, dried to obtain immediate-release granules; S2, Preparation of sustained-release granules: Arginine ibuprofen and filler are mixed evenly, binder solution is added to form soft material, granulated by sieve, and dried to obtain arginine ibuprofen drug-loaded core; Add the sustained-release agent and plasticizer to purified water, mix well, and obtain a sustained-release coating solution; The sustained-release coating solution was used to coat the arginine ibuprofen drug-carrying core to obtain sustained-release particles; S3, mix the immediate-release granules and the sustained-release granules evenly to obtain an arginine ibuprofen biphasic sustained-release formulation.

10. The method for preparing the arginine ibuprofen biphasic sustained-release formulation as described in claim 9, characterized in that, In S2, the coating is applied by bottom spraying in a fluidized bed, with an inlet air temperature of 40℃~50℃ and a material temperature of 35℃~42℃.

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