Ibuprofen-pseudoephedra sustained-release tablet and preparation method thereof

Abstract

The invention provides an ibuprofen, pseudoephedra and ephedra sustained release tablet and a preparation method, and belongs to the technical field of medicines, the ibuprofen, pseudoephedra and ephedra sustained release tablet is composed of a tablet core and a coating material, the tablet core is prepared from the following components in parts by weight: 57 to 59 parts of ibuprofen, 21.5 to 22.8 parts of pseudoephedrine hydrochloride, 23 to 25 parts of an adhesive, 15 to 18 parts of a sustained-release material, 3 to 5 parts of a filling agent and 1.2 to 1.9 parts of talcum powder. The prepared ibuprofen, pseudoephedra and ephedra sustained-release tablet is obvious in sustained-release effect, stable in drug sustained release, capable of relieving side effects generated by taking, high in storage stability and still good in sustained-release effect after being stored for a long time.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a sustained-release tablet of buprenorphine and pseudoephedrine and a preparation method thereof. Background Art

[0002] Ibuprofen extended-release tablets are a combination drug that is commonly used to relieve symptoms caused by colds or flu, such as headaches, fever, nasal congestion, etc. This drug contains two main ingredients: ibuprofen and pseudoephedrine hydrochloride. Because it contains these two ingredients at the same time, Ibuprofen extended-release tablets can help relieve a variety of discomforts.

[0003] However, ibuprofen and pseudoephedrine hydrochloride may cause a series of side effects, including gastrointestinal discomfort, peptic ulcers, renal damage, increased heart rate or palpitations, increased blood pressure, etc. When these two ingredients are used together, the incidence of the above side effects may increase, and other adverse reactions may occur.

[0004] However, the sustained-release effect of the ibuprofen sustained-release tablets currently on the market is not ideal, and the drug sustained-release is unstable, resulting in that the side effects are not well alleviated. Therefore, a ibuprofen sustained-release tablet and a preparation method are urgently needed. Summary of the invention

[0005] The purpose of the present invention is to provide a sustained-release tablet of buprenorphine and pseudoephedrine and a preparation method thereof.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] An ibuprofen and pseudoephedrine sustained-release tablet consists of a tablet core and a coating material, wherein the tablet core consists of the following components in parts by weight: 57-59 parts of ibuprofen, 21.5-22.8 parts of pseudoephedrine hydrochloride, 23-25 ​​parts of a binder, 15-18 parts of a sustained-release material, 3-5 parts of a filler and 1.2-1.9 parts of talc.

[0008] The adhesive is a mixture of polyoxyethylene water-soluble resin, hydroxypropyl methylcellulose and polyacrylic acid resin III in a weight ratio of 1: (1.2-1.4): (0.3-0.6).

[0009] Further, the hypromellose comprises a mixture of 1828 substituted hypromellose, 2208 substituted hypromellose and 2906 substituted hypromellose in a weight ratio of (0.5-0.8):(1.6-1.9):(0.2-0.4), all of which are purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd. and meet the pharmacopoeia standards.

[0010] Furthermore, the polyoxyethylene water-soluble resin comprises a mixture of WSR-301, WSR-N750 and WSR-303NF in a weight ratio of 1: (1.5-1.8): (0.2-0.4). Brand: POLYOX TM POLYOX TM .

[0011] Polyacrylic acid resin III, pharmaceutical grade, CAS No. 24938-16-7, was purchased from Shanxi Jinyang Pharmaceutical Excipients Co., Ltd.

[0012] Furthermore, the sustained-release material is a mixture of Eudragit RD 100, Eudragit NE 30D and Eudragit RS100 in a weight ratio of (0.2-0.5):1:(1.4-1.7).

[0013] Different from the sustained-release tablets of a single drug component, the sustained-release tablets of ibuprofen and pseudoephedrine hydrochloride contain two active ingredients, ibuprofen and pseudoephedrine hydrochloride, and the sustained-release effect design is indeed more challenging. The sustained-release effect of the ibuprofen and pseudoephedrine sustained-release tablets in the prior art is not ideal, mainly reflected in the fact that the sustained-release amount in the early stage is too large, which easily causes discomfort to the user. The present invention adds a binder and a sustained-release material of a specific composition to the tablet core, and the components act synergistically to improve the uniformity of the sustained-release effect. The present invention adds a binder and a sustained-release material of a specific composition to the tablet core, so that these components can cooperate with each other in the sustained-release process of ibuprofen and pseudoephedrine hydrochloride, and act together on the speed and mode of drug sustained-release. Through the synergistic effect, the drug sustained-release process can be made smoother, reducing the phenomenon of rapid sustained-release in the early stage, and also maintaining sustained-release for a long time, thereby achieving an ideal therapeutic effect.

[0014] Eudragit RD 100, a mixture of Eudragit RL and sodium hydroxymethylcellulose (9:1). Eudragit RS100, a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1). Eudragit NE 30D, a copolymer of ethyl acrylate and methyl methacrylate (2:1). Purchased from: Rohm Acrylic Resin (Eudragit), Germany.

[0015] Furthermore, the preparation method of the coating material comprises the following steps:

[0016] (1) 0.2-0.4 parts by weight of ethyl methacrylate, 1 part by weight of methyl methacrylate, 1.1-1.3 parts by weight of butyl methacrylate, 0.15-0.20 parts by weight of initiator, 0.25-0.31 parts by weight of emulsifier and 6-9 parts by weight of water are mixed and reacted at 50-55° C. for 2.5-3 hours;

[0017] (2) Continue to add 2-4 parts by weight of ethyl cellulose (Ethocel) TMThe mixture was added with 1.2-1.8 parts by weight of hydroxypropyl methylcellulose (hydroxypropyl methylcellulose K100LV, Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.), the temperature was raised to 65-67°C for reaction for 1.2-1.5h, then at 75-80°C for reaction for 3.5-3.8h, and cooled to room temperature to obtain a coating material.

[0018] In the actual research and development process, it was found that the sustained-release stability of the ibuprofen sustained-release tablets was easily reduced after long-term storage. The present invention uses a coating material with a sustained-release effect, which can synergize with the tablet core to improve the sustained-release stability of the ibuprofen sustained-release tablets after long-term storage. The coating material of the present invention can form a protective layer to prevent the influence of external factors such as air and moisture on the drug in the tablet core, thereby extending the shelf life of the drug; through the synergistic effect of the coating material and the sustained-release material and adhesive in the tablet core, the sustained-release stability of the drug after long-term storage can be significantly improved. Even after a period of storage, the drug can still be sustained-released according to the designed schedule, thereby ensuring the therapeutic effect.

[0019] Furthermore, the emulsifier is selected from one or more of sodium lauryl sulfate, polysorbate 80, and Span 80.

[0020] Furthermore, the emulsifier comprises sodium lauryl sulfate, polysorbate 80 and Span 80 in a weight ratio of (0.4-0.7):1:(1.3-1.6).

[0021] Furthermore, the initiator is ammonium persulfate.

[0022] Furthermore, the filler is selected from one or more of dextrin, corn starch, microcrystalline cellulose and mannitol.

[0023] Furthermore, the filler is a mixture of dextrin, corn starch, microcrystalline cellulose and mannitol in a weight ratio of 1: (1.2-1.4): (0.3-0.6).

[0024] The present invention provides a method for preparing a sustained-release tablet of buprenorphine and pseudoephedrine, comprising the following steps:

[0025] (1) Preparing a tablet core: ibuprofen, pseudoephedrine hydrochloride, a binder, a sustained-release material, a filler and talc are uniformly mixed, water is added to form a soft material, a micro-tablet is obtained using an extrusion spheronization machine, and the micro-tablet is dried to obtain a tablet core;

[0026] (2) Coating: Coating the tablet core with a coating material to obtain ibuprofen and pseudoephedrine sustained-release tablets.

[0027] Furthermore, the weight of the ibuprofen and pseudoephedrine sustained-release tablets is increased by 2-4% compared to the weight of the tablet core.

[0028] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0029] 1. The ibuprofen and pseudoephedrine sustained-release tablets prepared by the present invention have obvious sustained-release effect, stable drug sustained-release, can alleviate the side effects caused by taking the drug, and have high storage stability.

[0030] 2. The present invention adds a binder and a sustained-release material of a specific composition to the tablet core, and the components act synergistically to improve the uniformity of the sustained-release effect.

[0031] 3. The present invention uses a coating material with a sustained-release effect, which can work synergistically with the tablet core to improve the sustained-release stability of the ibuprofen and pseudoephedrine sustained-release tablets after long-term storage. DETAILED DESCRIPTION

[0032] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] The raw materials used in the present invention are purchased from the following manufacturers:

[0034] 1828 substituted hydroxypropyl methylcellulose, 2208 substituted hydroxypropyl methylcellulose and 2906 substituted hydroxypropyl methylcellulose were mixed and purchased from Xi'an Hongyao Pharmaceutical Excipients Co., Ltd. and met the pharmacopoeia standards.

[0035] WSR-301, WSR-N750 and WSR-303NF, purchased from brand: POLYOX TM POLYOX TM .

[0036] Polyacrylic acid resin III, pharmaceutical grade, CAS No. 24938-16-7, was purchased from Shanxi Jinyang Pharmaceutical Excipients Co., Ltd.

[0037] Eudragit RD 100, a mixture of Eudragit RL and sodium hydroxymethylcellulose (9:1). Eudragit RS100, a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1). Eudragit NE 30D, a copolymer of ethyl acrylate and methyl methacrylate (2:1). Purchased from: Rohm Acrylic Resin (Eudragit), Germany.

[0038] Ethyl cellulose, purchased from Ethocel TM Standard 10Premium.

[0039] Hydroxypropyl methylcellulose was purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd., Hydroxypropyl methylcellulose K100LV.

[0040] Example 1

[0041] The present embodiment provides an ibuprofen and pseudoephedrine sustained-release tablet, which consists of a tablet core and a coating material, wherein the tablet core consists of the following components in parts by weight: 58 parts of ibuprofen, 22 parts of pseudoephedrine hydrochloride, 24 parts of a binder, 16 parts of a sustained-release material, 4 parts of a filler and 1.6 parts of talc.

[0042] The adhesive is a mixture of polyoxyethylene water-soluble resin, hydroxypropyl methylcellulose and polyacrylic acid resin III in a weight ratio of 1:1.3:0.5.

[0043] The hypromellose comprises a mixture of 1828 substituted hypromellose, 2208 substituted hypromellose and 2906 substituted hypromellose in a weight ratio of 0.7:1.8:0.3.

[0044] The polyoxyethylene water-soluble resin includes a mixture of WSR-301, WSR-N750 and WSR-303NF in a weight ratio of 1:1.6:0.3.

[0045] The sustained-release material is a mixture of Eudragit RD 100, Eudragit NE 30D and Eudragit RS100 in a weight ratio of 0.4:1:1.6.

[0046] The filler is a mixture of dextrin, corn starch, microcrystalline cellulose and mannitol in a weight ratio of 1:1.3:0.5.

[0047] The preparation method of the coating material comprises the following steps:

[0048] (1) 0.3 parts by weight of ethyl methacrylate, 1 part by weight of methyl methacrylate, 1.2 parts by weight of butyl methacrylate, 0.18 parts by weight of initiator, 0.27 parts by weight of emulsifier and 7 parts by weight of water were mixed and reacted at 52° C. for 2.7 hours; the emulsifier included sodium lauryl sulfate, polysorbate 80 and Span 80 in a weight ratio of 0.5:1:1.5. The initiator was ammonium persulfate.

[0049] (2) Continue to add 3 parts by weight of ethyl cellulose and 1.4 parts by weight of hydroxypropyl methylcellulose, raise the temperature to 66° C. and react for 1.4 hours, then react at 77° C. for 3.6 hours, and cool to room temperature to obtain a coating material.

[0050] The preparation method of the ibuprofen and pseudoephedrine sustained-release tablets comprises the following steps:

[0051] (1) Preparing a tablet core: ibuprofen, pseudoephedrine hydrochloride, a binder, a sustained-release material, a filler and talc are uniformly mixed, water is added to form a soft material, a micro-tablet is obtained using an extrusion spheronization machine, and the micro-tablet is dried to obtain a tablet core;

[0052] (2) Coating: The core tablets are coated with a coating material to obtain ibuprofen and pseudoephedrine sustained-release tablets, wherein the weight ratio of the coating to the core tablets is 3:97.

[0053] Example 2

[0054] The present embodiment provides an ibuprofen and pseudoephedrine sustained-release tablet, which consists of a tablet core and a coating material, wherein the tablet core consists of the following components in parts by weight: 57 parts of ibuprofen, 22.8 parts of pseudoephedrine hydrochloride, 23 parts of a binder, 18 parts of a sustained-release material, 3 parts of a filler and 1.9 parts of talc.

[0055] The adhesive is a mixture of polyoxyethylene water-soluble resin, hydroxypropyl methylcellulose and polyacrylic acid resin III in a weight ratio of 1:1.2:0.6.

[0056] The hypromellose comprises a mixture of 1828 substituted hypromellose, 2208 substituted hypromellose and 2906 substituted hypromellose in a weight ratio of 0.8:1.9:0.2.

[0057] The polyoxyethylene water-soluble resin includes a mixture of WSR-301, WSR-N750 and WSR-303NF in a weight ratio of 1:1.5:0.2.

[0058] The sustained-release material is a mixture of Eudragit RD 100, Eudragit NE 30D and Eudragit RS100 in a weight ratio of 0.5:1:1.7.

[0059] The filler is a mixture of dextrin, corn starch, microcrystalline cellulose and mannitol in a weight ratio of 1:1.4:0.3.

[0060] The preparation method of the coating material comprises the following steps:

[0061] (1) 0.2 parts by weight of ethyl methacrylate, 1 part by weight of methyl methacrylate, 1.3 parts by weight of butyl methacrylate, 0.15 parts by weight of initiator, 0.31 parts by weight of emulsifier and 6 parts by weight of water were mixed and reacted at 55° C. for 3 hours; the emulsifier included sodium lauryl sulfate, polysorbate 80 and Span 80 in a weight ratio of 0.7:1:1.6. The initiator was ammonium persulfate.

[0062] (2) Continue to add 4 parts by weight of ethyl cellulose and 1.2 parts by weight of hydroxypropyl methylcellulose, raise the temperature to 67° C. and react for 1.5 hours, then react at 75° C. for 3.8 hours, and cool to room temperature to obtain a coating material.

[0063] The preparation method of the ibuprofen and pseudoephedrine sustained-release tablets comprises the following steps:

[0064] (1) Preparing a tablet core: ibuprofen, pseudoephedrine hydrochloride, a binder, a sustained-release material, a filler and talc are uniformly mixed, water is added to form a soft material, a micro-tablet is obtained using an extrusion spheronization machine, and the micro-tablet is dried to obtain a tablet core;

[0065] (2) Coating: The core tablets are coated with a coating material to obtain ibuprofen and pseudoephedrine sustained-release tablets, wherein the weight ratio of the coating to the core tablets is 3:97.

[0066] Comparative Example 1

[0067] The difference between this comparative example and Example 1 is that 24 parts of adhesive and 16 parts of sustained-release material are replaced by 20 parts of adhesive and 20 parts of sustained-release material.

[0068] Comparative Example 2

[0069] The difference between this comparative example and Example 1 is that the adhesive is a mixture of polyoxyethylene water-soluble resin, hydroxypropyl methylcellulose and polyacrylic acid resin III in a weight ratio of 1:1:1.

[0070] Comparative Example 3

[0071] The difference between this comparative example and Example 1 is that the hypromellose includes a mixture of 1828 substituted hypromellose, 2208 substituted hypromellose and 2906 substituted hypromellose in a weight ratio of 1:1:1.

[0072] Comparative Example 4

[0073] The difference between this comparative example and Example 1 is that the polyoxyethylene water-soluble resin includes a mixture of WSR-301, WSR-N750 and WSR-303NF in a weight ratio of 1:1:1.

[0074] Comparative Example 5

[0075] The difference between this comparative example and Example 1 is that the polyoxyethylene water-soluble resin comprises a mixture of WSR-301NF, WSR CoagulantNF and WSRN12K in a weight ratio of 1:1.6:0.3.

[0076] Comparative Example 6

[0077] The difference between this comparative example and Example 1 is that the sustained-release material is a mixture of Eudragit RD 100, Eudragit NE 30D and Eudragit RS100 in a weight ratio of 1:1:1.

[0078] Comparative Example 7

[0079] The difference between this comparative example and Example 1 is that: 0.3 parts by weight of ethyl methacrylate, 1 part by weight of methyl methacrylate, and 1.2 parts by weight of butyl methacrylate are replaced by: 1.2 parts by weight of ethyl methacrylate, 0.3 parts by weight of methyl methacrylate, and 1 part by weight of butyl methacrylate

[0080] Comparative Example 8

[0081] The difference between this comparative example and Example 1 is that: continuing to add 3 parts by weight of ethyl cellulose and 1.4 parts by weight of hypromellose is replaced by continuing to add 1.4 parts by weight of ethyl cellulose and 3 parts by weight of hypromellose.

[0082] Performance Testing

[0083] The performance of the Ibuprofen and Pseudoephedrine sustained-release tablets prepared in Examples 1-2 and Comparative Examples 1-8 was tested, and the control group was the Ibuprofen and Pseudoephedrine sustained-release tablets produced by Harbin Grale Pharmaceutical Co., Ltd.

[0084] 1. Dissolution The dissolution of ibuprofen and pseudoephedrine hydrochloride in artificial gastric juice (pH 1.4) was determined in reference to the four parts of the 2020 edition of the Chinese Pharmacopoeia. Each sample was sampled at 1h, 6h, 12h, 18h, and 24h. The results are shown in Table 1. In Table 1, A represents ibuprofen, B represents pseudoephedrine hydrochloride, and / in the table represents that no testing is performed at this time point.

[0085] Table 1 Dissolution of Buprofezin sustained-release tablets (%)

[0086]

[0087] 2. After the ibuprofen and pseudoephedrine sustained-release tablets were sealed and stored away from light for 6 months, the dissolution in artificial gastric juice (pH 1.4) was determined by the same method as above. The results are shown in Table 2, where A represents ibuprofen, B represents pseudoephedrine hydrochloride, and / in the table represents that no further testing was performed at this time point.

[0088] Table 2 Dissolution of Ibuprofen Sustained-Release Tablets after 6 Months of Storage (%)

[0089]

[0090] From the above performance test results, it can be seen that the sustained-release tablets of Examples 1-2 have good sustained-release effects, balanced sustained-release performance, can maintain a relatively stable sustained-release rate within 18 hours, and can achieve complete sustained-release within 24 hours. At the same time, the long-term stability is high. In particular, the comprehensive performance of Example 1 is the most outstanding, which is mainly due to the synergistic effect of the components of the sustained-release tablets of Ibuprofen.

[0091] The comparative examples, however, were significantly inferior to the embodiments in the corresponding performance tests because they did not adopt the necessary technical solutions. In comparative example 1, the ratio of the binder and the sustained-release material in the tablet core was changed, and it can be seen that the sustained-release effect of the Ibuprofen sustained-release tablets decreased, proving that the binder and the sustained-release material synergistically exerted an effect on the sustained-release effect of the Ibuprofen sustained-release tablets. The ratio schemes of the binder were not used in comparative examples 2-6, and it can be seen from the results that the sustained-release effect of the Ibuprofen sustained-release tablets decreased. The composition of the coating material prepared in comparative examples 7-8 was changed, and the storage stability of the Ibuprofen sustained-release tablets decreased. The commercially available Ibuprofen sustained-release tablets had a high initial sustained-release degree, and the sustained-release was basically complete within 12 hours, and the sustained-release effect decreased significantly after long-term storage. The above experimental results further prove the importance of the technical solution defined in the present invention for its technical effect.

[0092] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A sustained-release tablet of buprenorphine and pseudoephedrine, characterized in that: The tablet core is composed of a tablet core and a coating material, wherein the tablet core is composed of the following components in parts by weight: 57-59 parts of ibuprofen, 21.5-22.8 parts of pseudoephedrine hydrochloride, 23-25 ​​parts of a binder, 15-18 parts of a sustained-release material, 3-5 parts of a filler and 0.1-1.5 parts of talc; The adhesive is a mixture of polyoxyethylene water-soluble resin, hydroxypropyl methylcellulose and polyacrylic acid resin III in a weight ratio of 1: (1.2-1.4): (0.3-0.6); The hypromellose comprises a mixture of 1828 substituted hypromellose, 2208 substituted hypromellose and 2906 substituted hypromellose in a weight ratio of (0.5-0.8):(1.6-1.9):(0.2-0.4); The polyoxyethylene water-soluble resin comprises a mixture of WSR-301, WSR-N750 and WSR-303NF in a weight ratio of 1: (1.5-1.8): (0.2-0.4).

2. The sustained-release tablet of Ibuprofen and pseudoephedrine according to claim 1, characterized in that The sustained-release material is a mixture of Eudragit RD 100, Eudragit NE 30D and Eudragit RS100 in a weight ratio of (0.2-0.5):1:(1.4-1.7).

3. The sustained-release tablet of buprenorphine according to claim 1, characterized in that The preparation method of the coating material comprises the following steps: (1) 0.2-0.4 parts by weight of ethyl methacrylate, 1 part by weight of methyl methacrylate, 1.1-1.3 parts by weight of butyl methacrylate, 0.15-0.20 parts by weight of initiator, 0.25-0.31 parts by weight of emulsifier and 6-9 parts by weight of water are mixed and reacted at 50-55° C. for 2.5-3 hours; (2) Continue to add 2-4 parts by weight of ethyl cellulose and 1.2-1.8 parts by weight of hydroxypropyl methylcellulose, raise the temperature to 65-67° C. and react for 1.2-1.5 hours, then react at 75-80° C. for 3.5-3.8 hours, and cool to room temperature to obtain a coating material.

4. The sustained-release tablet of buprenorphine and pseudoephedrine according to claim 3, characterized in that: The emulsifier is selected from one or more of sodium lauryl sulfate, polysorbate 80, and Span 80.

5. The sustained-release tablet of buprenorphine and pseudoephedrine according to claim 4, characterized in that: The emulsifier includes sodium lauryl sulfate, polysorbate 80 and Span 80 in a weight ratio of (0.4-0.7):1:(1.3-1.6).

6. The sustained-release tablet of Ibuprofen and pseudoephedrine according to claim 3, characterized in that: The initiator is ammonium persulfate.

7. The sustained-release tablet of Ibuprofen and pseudoephedrine according to claim 1, characterized in that: The filler is selected from one or more of dextrin, corn starch, microcrystalline cellulose and mannitol.

8. The sustained-release tablet of Ibuprofen and pseudoephedrine according to claim 7, characterized in that: The filler is a mixture of dextrin, corn starch, microcrystalline cellulose and mannitol in a weight ratio of 1: (1.2-1.4): (0.3-0.6).

9. A method for preparing the sustained-release tablets of Ibuprofen and Pseudoephedrine according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Preparing a tablet core: ibuprofen, pseudoephedrine hydrochloride, a binder, a sustained-release material, a filler and talc are uniformly mixed, water is added to form a soft material, a micro-tablet is obtained using an extrusion spheronization machine, and the tablet core is obtained by drying; (2) Coating: Coating the tablet core with a coating material to obtain ibuprofen and pseudoephedrine sustained-release tablets.

10. The method for preparing the sustained-release tablets of Ibuprofen and Pseudoephedrine according to claim 9, characterized in that: The weight of the Ibuprofen sustained-release tablets is increased by 2-4% compared to the weight of the core tablets.

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