A kind of compound celecoxib capsule and preparation method thereof

Abstract

The present invention relates to a compound celecoxib capsule and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The compound celecoxib capsule of the present invention is composed of celecoxib, a cyperus rotundus peel extract, a filler, a lubricant, and a capsule shell. The present invention uses a combination of a cyperus rotundus peel extract and celecoxib to exert significant advantages in treating arthritis, especially in relieving inflammation and joint symptoms. Animal experiments show that the combined use can exert a therapeutic effect superior to that of celecoxib alone.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound celecoxib capsule and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] With the improvement of people's living standards, the incidence of bone and joint diseases has increased year by year, especially chronic diseases such as osteoarthritis and rheumatoid arthritis, which have a significant impact on the quality of life of patients. Traditional treatments mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, etc. Although they can effectively relieve pain and inflammation, long-term use may cause side effects such as gastrointestinal discomfort and kidney damage. Celecoxib is a selective COX-2 inhibitor, mainly used to relieve pain and inflammation, especially in the treatment of osteoarthritis and rheumatoid arthritis. It selectively inhibits cyclooxygenase-2 (COX-2) and reduces the production of prostaglandins, thereby effectively reducing inflammatory responses and pain. Compared with traditional nonsteroidal anti-inflammatory drugs (NSAIDs), celecoxib has a smaller inhibitory effect on COX-1, which makes it advantageous in reducing gastrointestinal side effects. However, long-term use still needs to pay attention to the increase in cardiovascular risk, so doctors will comprehensively evaluate the patient's health status when prescribing. However, single-ingredient drug treatments often have limited efficacy and cannot fully meet the needs of patients. For this reason, the research on compound preparations came into being, which enhances the efficacy and reduces side effects by combining multiple drugs.

[0004] There are examples in the prior art of using existing Chinese medicine preparations in combination with celecoxib to treat bone and joint diseases. However, since at least one additional Chinese medicine preparation is taken, the complexity of the patient's medication will increase and affect the patient's compliance (Yang Hui. Efficacy of Compound Bamboo-joint Ginseng Tablets Combined with Celecoxib Capsules in the Treatment of Knee Osteoarthritis [J]. Clinical Rational Drug Use, 2023, 16(18): 121-123).

[0005] At present, there are also cases of using Chinese herbal medicine extracts and celecoxib to make preparations. For example, Chinese patent publication number CN117243968A discloses a celecoxib compound preparation, including: 1-3 parts by weight of celecoxib, 3-6 parts by weight of yam polysaccharide, 5-15 parts by weight of cyclodextrin, 2-5 parts by weight of cellulose acetate peptide ester, 2-5 parts by weight of a mixture of hydroxypropyl methylcellulose and sodium alginate, 3-6 parts by weight of a mixture of polyvinyl pyrrolidone and sorbitol, 1-5 parts by weight of a disintegrant, 1-5 parts by weight of a filler, 0.5-2 parts by weight of a binder, and 0.2-1 parts by weight of a lubricant.

[0006] The present invention aims to provide a compound celecoxib capsule and a preparation method thereof, in order to achieve a more ideal clinical effect and improve the quality of life of patients by optimizing the formula and preparation process. Baomazipi is a common Chinese medicinal material, mainly derived from the bark of the plant Baomazi (also known as Baomazi tree, Baomazi wood), which has the effects of clearing the lungs and removing phlegm, relieving cough and relieving asthma. At present, its anti-inflammatory and analgesic effects have not been found, and there is no report on the combined use of Baomazipi and celecoxib. Summary of the invention

[0007] In order to overcome the deficiencies of the prior art, the present invention uses a Chinese herbal medicine extract and celecoxib to prepare a preparation, and provides a compound celecoxib capsule with significant effect in treating or relieving arthritis. Specifically, the technical scheme is as follows:

[0008] A compound celecoxib capsule is composed of 20 parts by weight of celecoxib, 2-12 parts by weight of a pyracantha bark extract, 5-15 parts by weight of a filler, 0.1-1 parts by weight of a lubricant, and a capsule shell.

[0009] Preferably, the compound celecoxib capsule is composed of 20 parts by weight of celecoxib, 8 parts by weight of the extract of Psoralea corylifolia bark, 10 parts by weight of a filler, and 0.5 parts by weight of a lubricant.

[0010] Preferably, the preparation method of the extract of Psoralea corylifolia is:

[0011] (1) Wash and chop the skin of the schizonepeta tenuifolia, add 6 to 8 times the mass of water, reflux at 75°C to 85°C for 1 to 2 hours, and extract the volatile oil;

[0012] (2) After extracting the volatile oil, soak the peel of the baomazi in a buffer solution of pH = 4.0 ~ 5.0 for 8 ~ 12 hours, filter, add 6 ~ 8 times the mass of water to the baomazi peel, heat to 80 ° C ~ 100 ° C for extraction, extract twice, each time for 1 ~ 2 hours, obtain the filtrate and filter residue, combine the two filtrates and set aside;

[0013] (3) After the filter residue obtained in step (2) is vacuum dried, 4 to 6 times the mass of 65% to 80% ethanol is added, and the mixture is heated to reflux at 50°C to 70°C for 1 to 2 hours. The mixture is filtered, and the obtained filtrate is combined with the filtrate obtained in step (2), concentrated by rotary evaporation under reduced pressure and heating, and the volatile oil described in step (1) is added and mixed until the relative density reaches 1.35 to 1.45, thereby obtaining the extract of the bark of the Chinese magnolia vine.

[0014] Further preferably, the buffer solution is selected from one of citric acid-sodium citrate buffer, potassium hydrogen phthalate-hydrochloric acid buffer, and disodium hydrogen phosphate-citric acid buffer.

[0015] Further preferably, the pH of the buffer solution is 4.0.

[0016] Further preferably, the relative density is 1.40.

[0017] Preferably, the filler is selected from one or more of starch, mannitol, microcrystalline cellulose, dextrin, and calcium hydrogen phosphate.

[0018] Preferably, the lubricant is selected from one or more of micro powder silica gel, magnesium stearate, magnesium lauryl sulfate, and hydrogenated vegetable oil.

[0019] The preparation method of the compound celecoxib capsule of the present invention is a preparation method of a conventional capsule preparation, comprising the following steps: taking a prescribed amount of a baicalensis peel extract, celecoxib, a filler, and a lubricant, mixing, granulating, granulating, drying, filling and sleeved in a capsule shell, and sealing to obtain the capsule.

[0020] The present invention also provides use of the compound celecoxib capsule in preparing a medicine for treating arthritis.

[0021] Compared with the prior art, the technical effects of the present invention are:

[0022] The combined use of the extract of the bark of the schizonepeta and celecoxib in the present invention has a significant advantage in treating arthritis, especially in relieving inflammation and joint symptoms. Animal experiments show that the combined use can exert a therapeutic effect superior to that of celecoxib alone.

[0023] The invention optimizes the preparation method of the extract of the scutellaria baicalensis peel, and the scutellaria baicalensis peel extract has a synergistic effect with celecoxib through certain components to enhance the anti-inflammatory effect of celecoxib. The introduction of the scutellaria baicalensis peel extract provides a new research direction for the combined use of natural plant extracts and traditional chemical drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The graphs show the changes in the width of the right knee joint of rats in each group.

[0025] Figure 2Figure 3 is a graph showing the GAGs content in the synovial tissue of the joints of rats in each group. DETAILED DESCRIPTION

[0026] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0027] Example 1

[0028] A baumazi peel extract and a preparation method thereof, the preparation method comprising the following steps:

[0029] (1) Wash and chop 100g of the skin of the schizonepeta tenuifolia, add water 7 times the weight of the skin of the schizonepeta tenuifolia, reflux at 80°C for 1.5h, and extract the volatile oil;

[0030] (2) After extracting the volatile oil, soak the peel of the baomazizi in a pH = 4.5 potassium hydrogen phthalate-hydrochloric acid buffer for 10 hours, filter, add 7 times the water to the baomazizi peel and heat to 90°C for extraction, extract twice, each time for 1.5 hours, obtain the filtrate and the residue, combine the two filtrates and set aside;

[0031] (3) After the filter residue obtained in step (2) is vacuum dried, 5 times the mass of 75% ethanol is added, and the mixture is heated to reflux at 60° C. for extraction for 1.5 h. The mixture is filtered, and the obtained filtrate is combined with the filtrate obtained in step (2), and concentrated by rotary evaporation under reduced pressure and heating. The volatile oil described in step (1) is added, and the mixture is concentrated to a relative density of 1.40 to obtain the extract of the bark of the Chinese magnolia vine.

[0032] Example 2

[0033] A baumazi peel extract and a preparation method thereof, the preparation method comprising the following steps:

[0034] (1) Wash and chop 100g of the skin of the schizonepeta tenuifolia, add water 6 times the weight of the skin of the schizonepeta tenuifolia, reflux at 75°C for 1h, and extract the volatile oil;

[0035] (2) After extracting the volatile oil, soak the peel of the baomazi in a pH = 4.0 citric acid-sodium citrate buffer for 8 hours, filter, add 6 times the mass of water to the baomazi peel, heat to 80°C for extraction, extract twice, each time for 1 hour, obtain the filtrate and the residue, combine the two filtrates and set aside;

[0036] (3) After the filter residue is vacuum dried, add 4 times the mass of 65% ethanol, heat and reflux at 50°C for extraction for 1 hour, filter, combine the obtained filtrate with the filtrate obtained in step (2), concentrate by rotary evaporation under reduced pressure, add the volatile oil described in step (1), and concentrate to a relative density of 1.35 to obtain the extract of the bark of the Chinese magnolia vine.

[0037] Example 3

[0038] A baumazi peel extract and a preparation method thereof, the preparation method comprising the following steps:

[0039] (1) Wash and chop 100g of the skin of the schizonepeta tenuifolia, add water 8 times the weight of the skin of the schizonepeta tenuifolia, reflux at 85°C for 2h, and extract the volatile oil;

[0040] (2) After extracting the volatile oil, soak the peel of the baomazi in a sodium dihydrogen phosphate-citric acid buffer solution with a pH of 5.0 for 12 h, filter, add 8 times the mass of water to the peel of the baomazi, heat to 100°C for extraction, extract twice, each time for 2 h, obtain the filtrate and the residue, combine the two filtrates and set aside;

[0041] (3) After the filter residue obtained in step (2) is vacuum dried, add 6 times the mass of 80% ethanol, heat and reflux at 70°C for extraction for 2 hours, filter, combine the obtained filtrate with the filtrate obtained in step (2), concentrate by rotary evaporation under reduced pressure, add the volatile oil described in step (1), and concentrate to a relative density of 1.45 to obtain the extract of the bark of the thorn tree.

[0042] Comparative Example 1

[0043] A baumazi peel extract and a preparation method thereof, the preparation method comprising the following steps:

[0044] (1) Wash and chop 100g of the skin of the schizonepeta tenuifolia, add water 7 times the weight of the skin of the schizonepeta tenuifolia, reflux at 80°C for 1.5h, and extract the volatile oil;

[0045] (2) After extracting the volatile oil, add twice the weight of water to the bark of the thorny tree, adjust the pH to 4.0 with an appropriate amount of hydrochloric acid, soak for 10 hours, filter, add 7 times the weight of water to the bark of the thorny tree, heat to 90°C for extraction, extract twice, each time for 1.5 hours, obtain the filtrate and the residue, combine the two filtrates and set aside;

[0046] (3) After the filter residue obtained in step (2) is vacuum dried, 5 times the mass of 75% ethanol is added, and the mixture is heated to reflux at 60° C. for extraction for 1.5 h. The mixture is filtered, and the obtained filtrate is combined with the filtrate obtained in step (2), and concentrated by rotary evaporation under reduced pressure and heating. The volatile oil described in step (1) is added, and the mixture is concentrated to a relative density of 1.40 to obtain the extract of the bark of the Chinese magnolia vine.

[0047] Comparative Example 2

[0048] A baumazi peel extract and a preparation method thereof, the preparation method comprising the following steps:

[0049] (1) Wash and chop 100 g of the skin of the schizonepeta tenuifolia, add water 7 times the weight of the skin of the schizonepeta tenuifolia, and reflux at 80°C for 1.5 h to extract the volatile oil;

[0050] (2) After extracting the volatile oil, add 7 times the weight of water to the peel of the baomazizi, heat it to 90°C and extract it twice, each time for 1.5 hours, to obtain the filtrate and the residue, and combine the two filtrates for later use;

[0051] (3) After the filter residue obtained in step (2) is vacuum dried, 5 times the mass of 75% ethanol is added, and the mixture is heated to reflux at 60° C. for extraction for 1.5 h. The mixture is filtered, and the obtained filtrate is combined with the filtrate obtained in step (2), and concentrated by rotary evaporation under reduced pressure and heating. The volatile oil described in step (1) is added, and the mixture is concentrated to a relative density of 1.40 to obtain the extract of the bark of the Chinese magnolia vine.

[0052] Example 4

[0053] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 1:

[0054] Table 1. Formula of compound celecoxib capsules

[0055]

[0056] Preparation method:

[0057] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0058] Example 5

[0059] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 2:

[0060] Table 2. Formula of compound celecoxib capsules

[0061]

[0062] Preparation method:

[0063] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0064] Example 6

[0065] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 3:

[0066] Table 3. Formula of compound celecoxib capsules

[0067]

[0068] Preparation method:

[0069] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0070] Comparative Example 3

[0071] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 4:

[0072] Table 4. Formula of compound celecoxib capsules

[0073]

[0074] Preparation method:

[0075] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0076] Comparative Example 4

[0077] A commercially available celecoxib capsule with national medicine standard number HJ20140106.

[0078] Comparative Example 5

[0079] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 5:

[0080] Table 5. Formula of compound celecoxib capsules

[0081]

[0082] Preparation method:

[0083] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0084] Comparative Example 6

[0085] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 6:

[0086] Table 6. Formula of compound celecoxib capsules

[0087]

[0088] Preparation method:

[0089] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0090] Comparative Example 7

[0091] A compound celecoxib capsule (100 capsules), the formula of which is shown in Table 7:

[0092] Table 7. Formula of compound celecoxib capsules

[0093]

[0094] Preparation method:

[0095] Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

[0096] Pharmacodynamics of compound celecoxib capsule on arthritis in rats

[0097] SD rats, SPF grade, weighing 180-220g, experimental animal license number: SYXK (Lu) 20180008, were adaptively fed for 1 week under standard conditions before the experiment. The rat osteoarthritis model was established by papain induction method: several rats were taken, 10% papain and 0.03mol / l L-cysteine ​​were mixed in a ratio of 1:1, and allowed to stand for 30 minutes. On days 0, 3, and 6 of the experiment, 0.2ml of papain mixed solution was injected into the knee joint cavity of the rats to induce an osteoarthritis model. The rats with successful modeling were divided into model group, Example 4 group, Example 5 group, Example 6 group, comparison group 1, comparison group 2, comparison group 3, comparison group 4, comparison group 5, comparison example 6 group, and horse mazi peel extract group, with 10 rats in each group. The 10 rats in the blank group were injected with an equal volume of saline.

[0098] The rats in each treatment group were gavaged with the corresponding drug (calculated as celecoxib, 18 mg / kg), the pyralis bark extract group was given 14.4 mg / kg of the pyralis bark extract of Example 1, and the blank group and the model group were gavaged with an equal amount of normal saline, once a day, for 21 days.

[0099] Test 1: Changes in rat knee joint width

[0100] In the pharmacodynamics experiment of osteoarthritis rats, the change of knee joint width is an important biological indicator, which is often used to evaluate the effect of joint pathological changes and drug treatment. The width of the right knee joint of rats was measured before administration and on the 5th, 10th, 15th and 21st day of administration (mm). The degree of joint swelling (mm) = the width of the knee joint after administration (mm) - the width of the knee joint before administration (mm).

[0101] Figure 1The width of the right knee joint of each group of rats changes. In the pharmacodynamics experiment, the variation of the knee joint width can be used to assess the inhibitory effect of the drug on joint effusion, reflect articular cartilage damage and bone change, and evaluate the mitigation effect of inflammatory reaction. The increase of knee joint width is usually caused by edema and inflammation of the synovium. In the drug treatment process, embodiment 4 groups, embodiment 5 groups, embodiment 6 groups can significantly alleviate synovitis or edema, and the knee joint width has an obvious trend of reduction, reflecting that the compound celecoxib capsule of the present invention relieves the effect of osteoarthritis.

[0102] Test 2: IL-4, IgE, and TNF-γ levels in rat synovial fluid

[0103] The levels of IL-4, IgE, and TNF-γ in the rat joint fluid after administration were measured by ELISA. The results are shown in Table 8.

[0104] Table 8 IL-4, IgE, and TNF-γ levels in rat synovial fluid

[0105]

[0106] Compared with the model group, * P <0.01;

[0107] Compared with the comparative example 4 group, # P <0.01;

[0108] Compared with the group of baicalensis peel extract, @ P <0.01;

[0109] The data in Table 8 show that the compound celecoxib capsules of Examples 4 to 6 of the present invention have a certain regulatory effect on the indicators IL-4, IgE and TNF-γ compared with the model group, indicating that the drugs of the present invention have a significant improvement effect on the inflammatory response of osteoarthritis.

[0110] Test 3: GAGs content in rat joint synovial tissue

[0111] After administration, the synovial tissue of both knee joints of rats was obtained, quickly frozen in liquid nitrogen and then stored at -80°C. An appropriate amount of synovial tissue was taken, added with ice-cold physiological saline, placed in an ice bath, and prepared into 2% synovial tissue homogenate using a tissue homogenizer, then centrifuged at 4°C and 3500 rpm for 10 minutes, the supernatant was collected, and the content of glycosaminoglycans (GAGs) in the synovial tissue of the joint was determined according to the operating steps of the dimethyl methylene blue spectrophotometry instruction manual.

[0112] GAGs are one of the main structural components of articular cartilage and synovium, and have the functions of lubrication, pressure resistance and promoting joint health. Changes in the content of GAGs in joint synovial tissue can reflect the health status of synovium and cartilage, inflammatory response and the repair effect of drugs. Figure 2 is the content of GAGs in the synovial tissue of the joints of the rats in each group. Compared with the rats in the model group, the content of GAGs in the synovial tissue of the joints of the rats in Examples 4 to 6 was significantly different. P <0.01, compared with the rats in the control group 4, the GAGs content in the synovial tissue of the rats in the examples 4 to 6 groups was significantly different, P <0.01, compared with the rats in the group of rats in the extract of Psoralea corylifolia, the content of GAGs in the synovial tissue of the rats in the groups of Examples 4 to 6 was significantly different, P <0.01.

[0113] In summary, the present invention verified the therapeutic effect of the compound celecoxib capsule of the present invention on arthritis model rats through indicators such as changes in rat knee joint width, IL-4, IgE, TNF-γ levels in rat synovial fluid, and GAGs content in rat synovial joint tissue. The overall result shows that the extract of the bark of the schizonepeta itself has no obvious therapeutic or alleviating effect on arthritis, but when the extract of the bark of the schizonepeta is used in combination with celecoxib in a certain proportion, the therapeutic effect of arthritis is better than that of celecoxib alone.

[0114] The above data were statistically analyzed using SPSS 22.0 software, and the quantitative data were analyzed using ( One-way analysis of variance was used for comparison among multiple groups, and independent sample T test was used for analysis between two groups. P The difference was statistically significant when the value was <0.05.

Claims

1. A compound celecoxib capsule, characterized in that, The compound celecoxib capsule is composed of 20 parts by weight of celecoxib, 2-12 parts by weight of a pyracantha bark extract, 5-15 parts by weight of a filler, 0.1-1 parts by weight of a lubricant, and a capsule shell; The preparation method of the scutellaria baicalensis peel extract is as follows: (1) Wash and chop the baomazi peel, add 6 to 8 times the mass of water of the baomazi peel, reflux at 75℃ to 85℃ for 1 to 2 hours, and extract the volatile oil; (2) After extracting the volatile oil, soak the peel of the baomazi in a buffer solution of pH = 4.0 ~ 5.0 for 8 ~ 12 hours, filter, add 6 ~ 8 times the mass of water to the baomazi peel, heat to 80 ° C ~ 100 ° C for extraction, extract twice, each time for 1 ~ 2 hours, obtain the filtrate and filter residue, combine the two filtrates and set aside; (3) After the filter residue obtained in step (2) is vacuum dried, 4 to 6 times the mass of 65% to 80% ethanol is added, and the mixture is heated to reflux at 50°C to 70°C for 1 to 2 hours, filtered, and the obtained filtrate is combined with the filtrate obtained in step (2), concentrated by rotary evaporation under reduced pressure and heating, and the volatile oil described in step (1) is added and mixed, and concentrated to a relative density of 1.35 to 1.45 to obtain the extract of the bark of the Chinese mackerel; The buffer solution is selected from one of citric acid-sodium citrate buffer, potassium hydrogen phthalate-hydrochloric acid buffer, and disodium hydrogen phosphate-citric acid buffer.

2. The compound celecoxib capsule according to claim 1, characterized in that The buffer solution has a pH of 4.

0.

3. The compound celecoxib capsule according to claim 1, characterized in that: The relative density is 1.

40.

4. The compound celecoxib capsule according to claim 1, characterized in that: The compound celecoxib capsule is composed of 20 parts by weight of celecoxib, 8 parts by weight of the extract of Psoralea corylifolia, 10 parts by weight of a filler, and 0.5 parts by weight of a lubricant.

5. The compound celecoxib capsule according to claim 1, characterized in that: The filler is selected from one or more of starch, mannitol, microcrystalline cellulose, dextrin, and calcium hydrogen phosphate.

6. The compound celecoxib capsule according to claim 1, characterized in that: The lubricant is selected from one or more of micro powder silica gel, magnesium stearate, magnesium lauryl sulfate, and hydrogenated vegetable oil.

7. A method for preparing the compound celecoxib capsule according to claim 1, characterized in that: The preparation method is as follows: Take the prescribed amount of the extract of the baicalensis bark, celecoxib, a filler and a lubricant, mix them, granulate them, shape them, dry them, fill them into a capsule shell, and seal them to obtain the product.

8. Use of the compound celecoxib capsule according to claim 1 in preparing a drug for treating arthritis.

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