An amino glucoside sulfate composition, its preparation method and its use

Abstract

The present application relates to a kind of glucosamine sulfate compositions, with percentage by weight, composition is made of glucosamine sulfate sodium chloride double salt 58.0%-90.0%, diluent 8.0%-40.0% and lubricant 2.0%-6.0%.The present application scientifically screens the components and proportion of composition, and the advantages such as high stability, good batch dissolution and batch dissolution uniformity, high bioavailability of prepared composition are provided for the technical support of clinical drug effectiveness and safety.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a glucosamine sulfate composition, a preparation method thereof and application thereof. BACKGROUND

[0002] Osteoarthritis is a common chronic pain disease, the main causes include abnormal proteoglycan biosynthesis leading to degenerative joint cartilage, pathological manifestations include chronic pain and loss of mobility, severe osteoarthritis even affects the quality of life of patients. With the increasing degree of global population aging, the prevalence of osteoarthritis shows an upward trend. The etiology of primary osteoarthritis is not clear. Secondary osteoarthritis is often induced by other causes (such as trauma, rheumatoid arthritis, neuropathic disorders, endocrine disorders, etc.). There are more than 300 million osteoarthritis patients worldwide. The overall prevalence of primary osteoarthritis in people over 40 years old in China is more than 46.3%.

[0003] D-glucosamine is a normal constituent of cartilage matrix polysaccharide chains and joint fluid glucosamine, which can stimulate chondrocytes to synthesize physiological multimeric structure of proteoglycan (such as polyglucosamine and proteoglycan, etc.), stimulate synoviocytes to synthesize hyaluronic acid, also can inhibit the activity of damaged cartilage enzymes (such as collagenase and phospholipase A2), and can prevent the production of superoxide free radicals in damaged tissues and cells, delay the progression of osteoarthritis, inhibit lysosomal activity and have anti-inflammatory effect, which can be used to improve joint activity and relieve pain, and is widely used for prevention and treatment of systemic bone and joint (including knee joint, hip joint, spine, shoulder joint, hand and wrist, ankle joint, etc.) inflammation, its safety and effectiveness have been widely verified. Glucosamine sulfate capsules are used for prevention and treatment of primary and secondary osteoarthritis, but its dissolution and stability need to be improved. Therefore, it is urgent to develop drugs with improved dissolution and stability to meet the effectiveness and safety requirements of clinical medication. SUMMARY

[0004] The present application aims to provide a glucosamine sulfate composition, which consists of 58.0%-90.0% of glucosamine sulfate sodium chloride complex salt with the structure shown in formula I, 8.0%-40.0% of diluent and 2.0%-6.0% of lubricant, by weight percentage.

[0005]

[0006] In the preferred technical solution of the present application, the diluent is selected from any one or combination of lactose, starch, corn starch, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, sugar powder, dextrin, sodium starch glycolate, sodium carboxymethyl starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose.

[0007] In the preferred technical solution of the present application, the lubricant is selected from any one or combination of talc, micronized silica gel, colloidal silicon dioxide, aluminum hydroxide, sodium dodecyl sulfate.

[0008] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 58.0%-90.0%, lactose 3.0%-15.0%, corn starch 5.0%-25.0%, and talc 2.0%-6.0% by weight percentage.

[0009] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 70.0%-85.0%, lactose 3.5.0%-11.0%, corn starch 6.25%-16.25%, and talc 2.50%-3.50% by weight percentage.

[0010] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 78.50%, lactose 7.25%, corn starch 11.25%, and talc 3.0% by weight percentage.

[0011] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 78.50%, lactose 10%, corn starch 8%, and talc 3.5% by weight percentage.

[0012] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 78.50%, lactose 3.5%, corn starch 14.5%, and talc 3.5% by weight percentage.

[0013] In the preferred technical solution of the present application, the composition consists of glucosamine sulfate sodium chloride double salt 78.50%, lactose 11%, corn starch 8%, and talc 2.5% by weight percentage.

[0014] In the preferred technical solution of the present application, the particle size distribution of the glucosamine sulfate sodium chloride double salt in the composition is D10=60-85μm, D50=130-170μm, D90=330-380μm, preferably D10=75μm, D50=150μm, D90=355μm.

[0015] In the preferred technical scheme of the present application, the lactose in the composition is passed through a 70-120 mesh sieve, preferably a 85-100 mesh sieve.

[0016] In the preferred technical scheme of the present application, the preparation of the composition comprises the following steps: passing the glucosamine sulfate sodium chloride double salt through a 40-50 mesh sieve, and then uniformly mixing with the required amount of diluent and wetting agent.

[0017] In the preferred technical scheme of the present application, the glucosamine sulfate sodium chloride double salt and lactose are passed through a 40-50 mesh sieve, respectively, and then uniformly mixed with the required amount of corn starch and talc.

[0018] In the preferred technical scheme of the present application, the mixing condition is 5-15 revolutions / min*10-30 min, preferably 10 revolutions / min*20 min.

[0019] In the preferred technical scheme of the present application, the composition is an oral preparation, preferably any one of tablets, capsules, granules, and pills.

[0020] In the preferred technical scheme of the present application, the bulk density of the composition is 0.7-0.9 g / ml, preferably 0.8-0.86 g / ml.

[0021] In the preferred technical scheme of the present application, the composition is filled into capsules, and the filling speed of the capsules is 900-1200 capsules / min, preferably 1000-1100 capsules / min.

[0022] The present application aims to provide a preparation method of a glucosamine sulfate composition, which comprises, by weight percentage, 58.0%-90.0% of glucosamine sulfate sodium chloride double salt, 8.0%-40.0% of diluent, and 2.0%-6.0% of lubricant, and the method comprises the following steps: passing the glucosamine sulfate sodium chloride double salt through a 40-50 mesh sieve, and then uniformly mixing with the required amount of diluent and wetting agent.

[0023] In the preferred technical scheme of the present application, the diluent is selected from any one or combination of lactose, starch, corn starch, pre-gelatinized starch, modified starch, hydroxypropyl starch, potato starch, sugar powder, dextrin, sodium starch glycolate, sodium carboxymethyl starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, ethyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl methyl cellulose.

[0024] In the preferred technical scheme of the present application, the lubricant is selected from any one or combination of talc, micronized silica gel, colloidal silicon dioxide, aluminum hydroxide, and sodium dodecyl sulfate.

[0025] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 58.0%-90.0%, lactose 3.0%-15.0%, corn starch 5.0%-25.0%, and talc 2.0%-6.0% by weight percentage.

[0026] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 70.0%-85.0%, lactose 3.5.0%-11.0%, corn starch 6.25%-16.25%, and talc 2.50%-3.50% by weight percentage.

[0027] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 78.50%, lactose 7.25%, corn starch 11.25%, and talc 3.0% by weight percentage.

[0028] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 78.50%, lactose 10%, corn starch 8%, and talc 3.5% by weight percentage.

[0029] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 78.50%, lactose 3.5%, corn starch 14.5%, and talc 3.5% by weight percentage.

[0030] In the preferred technical solution of the present application, the composition is composed of glucosamine sulfate sodium chloride double salt 78.50%, lactose 11%, corn starch 8%, and talc 2.5% by weight percentage.

[0031] In the preferred technical solution of the present application, the particle size distribution of the glucosamine sulfate sodium chloride double salt in the composition is D10=60-85 μm, D50=130-170 μm, and D90=330-380 μm, preferably D10=75 μm, D50=150 μm, and D90=355 μm.

[0032] In the preferred technical solution of the present application, the lactose in the composition is sieved through a 70-120 mesh sieve, preferably a 85-100 mesh sieve.

[0033] In the preferred technical solution of the present application, the glucosamine sulfate sodium chloride double salt and lactose are sieved through a 40-50 mesh sieve, respectively, and then uniformly mixed with the required amount of corn starch and talc to obtain the composition.

[0034] In the preferred technical solution of the present application, the mixing condition is 5-15 revolutions / min*10-30 min, preferably 10 revolutions / min*20 min.

[0035] In a preferred embodiment of the present invention, the composition is an oral preparation, preferably any one of tablets, capsules, granules, or pills.

[0036] In a preferred embodiment of the present invention, the bulk density of the composition is 0.7-0.9 g / ml, preferably 0.8-0.86 g / ml.

[0037] In a preferred embodiment of the present invention, the composition is filled into capsules at a filling rate of 900-1200 capsules / min, preferably 1000-1100 capsules / min.

[0038] Another object of the present invention is to provide the use of the glucosamine sulfate composition of the present invention in the preparation of a medicament for the prevention and treatment of primary or secondary osteoarthritis.

[0039] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0040] Compared with the prior art, the present invention has the following beneficial technical effects:

[0041] 1. The present invention scientifically screens the components and proportions of the composition, and the resulting composition has the advantages of high stability, good intra-batch and inter-batch dissolution uniformity, and high bioavailability, providing technical assurance for the effectiveness and safety of clinical drug use.

[0042] 2. The glucosamine sulfate capsules of the present invention have the advantages of good appearance, smooth capsules, tight locking, and low content variation.

[0043] 3. The preparation method of the present invention has the advantages of simple operation, high yield, better cost and suitability for industrial production. Detailed Implementation

[0044] The following detailed explanation and description of the present invention, in conjunction with specific embodiments, does not limit the scope of protection of the present invention.

[0045] Example 1 Preparation of the glucosamine sulfate composition of the present invention

[0046] The composition of the composition is as follows:

[0047]

[0048] The preparation of the composition includes the following steps:

[0049] (1) Pass the glucosamine sulfate sodium chloride double salt and lactose through a 40-mesh vibrating sieve;

[0050] (2) Weigh the required amounts of glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc, mix them evenly (15 rpm * 15 min), and then fill the resulting composition (bulk density of about 0.7 g / ml) into capsules (1000 capsules / min), 400 mg / capsule.

[0051] Example 2 Preparation of the glucosamine sulfate composition of the present invention

[0052] The composition of the composition is as follows:

[0053]

[0054]

[0055] The preparation of the composition includes the following steps:

[0056] (1) Pass the glucosamine sulfate sodium chloride double salt and lactose through a 40-mesh vibrating sieve;

[0057] (2) Weigh the required amounts of glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc, mix them evenly (10 rpm * 20 min), and then fill the prepared composition (bulk density of about 0.8 g / ml) into capsules (1100 capsules / min), 400 mg / capsule, and you have the product.

[0058] Example 3 Preparation of the glucosamine sulfate composition of the present invention

[0059] The composition of the composition is as follows:

[0060]

[0061] The preparation of the composition includes the following steps:

[0062] (1) Pass the glucosamine sulfate sodium chloride double salt and lactose through a 40-mesh vibrating sieve;

[0063] (2) Weigh the required amounts of glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc, mix them evenly (10 rpm * 20 min), and then fill the prepared composition (bulk density of about 0.86 g / ml) into capsules (1100 capsules / min), 400 mg / capsule, and you have the product.

[0064] Example 4 Preparation of the glucosamine sulfate composition of the present invention

[0065] The composition of the composition is as follows:

[0066]

[0067] The preparation of the composition includes the following steps:

[0068] (1) Pass the glucosamine sulfate sodium chloride double salt and lactose through a 40-mesh vibrating sieve;

[0069] (2) Weigh the required amounts of glucosamine sulfate sodium chloride double salt, lactose, corn starch and talc, mix them evenly (10 rpm * 20 min), and then fill the resulting composition (bulk density of about 0.9 g / ml) into capsules (1100 capsules / min), 400 mg / capsule, and you have the product.

[0070] Comparative Example 1 Preparation of glucosamine sulfate composition

[0071] The composition of the composition is as follows:

[0072]

[0073] The preparation of the composition includes the following steps:

[0074] (1) Pass the glucosamine sulfate sodium chloride double salt and lactose through a 40-mesh vibrating sieve;

[0075] (2) Weigh the required amounts of glucosamine sulfate sodium chloride double salt, lactose, corn starch, talc and magnesium stearate, mix them evenly (15 rpm * 15 min), and then fill the prepared composition (bulk density of about 0.7 g / ml) into capsules (1000 capsules / min), 400 mg / capsule, to obtain the final product.

[0076] Test Example 1 Dissolution test of the glucosamine sulfate composition of the present invention

[0077] The dissolution rate of the glucosamine sulfate composition of the present invention was investigated with reference to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms" and the "Guidelines for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms".

[0078] The glucosamine sulfate compositions of Example 1 and Comparative Example 1 were placed under accelerated testing conditions (40℃±2℃ / 75%RH±5%RH) for 6 months. Samples were taken at day 0, month 3, and the end of month 6. The dissolution rate in four dissolution media (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution, and water) was investigated using the paddle method (with a settling basket) at 50 rpm and a medium volume of 900 mL. The results are shown in Tables 1-2.

[0079] Table 1 Dissolution test of the glucosamine sulfate composition in Example 1

[0080]

[0081]

[0082] Table 2 Dissolution test of the glucosamine sulfate composition in Comparative Example 1

[0083]

[0084]

[0085] The glucosamine sulfate composition of Example 1, after being placed under accelerated conditions for 6 months, showed a slight decrease in dissolution rate, with a dissolution rate greater than 85% at 15 minutes, indicating rapid dissolution. In contrast, the glucosamine sulfate composition of Comparative Example 1, after being placed under accelerated conditions for 6 months, showed a significant decrease in dissolution rate, failing to reach maximum dissolution even at 45 minutes.

[0086] Test Example 2 Dissolution test of the glucosamine sulfate composition of the present invention

[0087] The glucosamine sulfate compositions from Examples 2-4 were sampled using a paddle method (with a settling basket) at 50 rpm for 900 mL at 5 min, 10 min, and 30 min. The dissolution curves of the glucosamine sulfate compositions from Examples 2-4 in the dissolution medium (0.1 mol / L hydrochloric acid solution) were investigated using HPLC (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) at a wavelength of 344 nm. The results are shown in Table 3. The dissolution rate of the glucosamine sulfate compositions from Examples 2-4 was over 85% within 10 min.

[0088] Table 3

[0089]

[0090] Test Example 3 Dissolution and stability studies of the glucosamine sulfate composition of the present invention

[0091] The glucosamine sulfate composition of Example 1 and the glucosamine sulfate composition of Comparative Example 1 were placed under accelerated testing conditions (40℃±2℃ / 75%RH±5%RH) for 6 months. Samples of the glucosamine sulfate composition of Example 1 were taken at the end of 0 days, 1 month, 2 months, 3 months, and 6 months, respectively, and samples of the glucosamine sulfate composition of Comparative Example 1 were taken at the end of 0 days, 3 months, and 6 months, respectively. The dissolution rate in water was determined according to the dissolution and release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), and related substances were detected according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The results are shown in Tables 4-5.

[0092] Table 4. Results of dissolution and stability studies of the glucosamine sulfate composition in Example 1.

[0093]

[0094] Table 5. Results of dissolution and stability studies of the glucosamine sulfate composition in Comparative Example 1.

[0095]

[0096] The glucosamine sulfate composition of Comparative Example 1, after being placed under accelerated conditions for 6 months, showed a significant increase in the detection of related substances (fructosamine, 2,5-deoxyfructosamine) and total impurities, and a significant decrease in dissolution, all exceeding the limits. The glucosamine sulfate composition of this invention exhibits excellent dissolution and stability.

[0097] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A glucosamine sulfate composition, the composition consisting of glucosamine sulfate sodium chloride complex salt of the structure shown in Formula I 58.0%-90.0%, lactose 3.0%-15.0%, corn starch 5.0%-25.0% and talc 2.0%-6.0% by weight percentage, the particle size distribution of the glucosamine sulfate sodium chloride complex salt in the composition is D10=60-85 μm, D50=130-170 μm, D90=330-380 μm. (Formula I).

2. The composition of claim 1, the composition consisting of glucosamine sulfate sodium chloride complex salt 70.0%-85.0%, lactose 3.5.0%-11.0%, corn starch 6.25%-16.25% and talc 2.50%-3.50% by weight percentage.

3. The composition of claim 2, the composition consisting of glucosamine sulfate sodium chloride complex salt 78.50%, lactose 7.25%, corn starch 11.25% and talc 3.0% by weight percentage.

4. The composition of claim 2, the composition consisting of glucosamine sulfate sodium chloride complex salt 78.50%, lactose 10%, corn starch 8% and talc 3.5% by weight percentage.

5. The composition of claim 2, the composition consisting of glucosamine sulfate sodium chloride complex salt 78.50%, lactose 3.5%, corn starch 14.5% and talc 3.5% by weight percentage.

6. The composition of claim 2, the composition consisting of glucosamine sulfate sodium chloride complex salt 78.50%, lactose 11%, corn starch 8% and talc 2.5% by weight percentage.

7. The composition of claim 1, the particle size distribution of the glucosamine sulfate sodium chloride complex salt in the composition is D10=75 μm, D50=150 μm, D90=355 μm.

8. The composition of claim 1, the lactose in the composition is passed through a 70-120 mesh sieve.

9. The composition of claim 8, the lactose in the composition is passed through a 85-100 mesh sieve.

10. The composition of any one of claims 1-9, the preparation of the composition comprises the following steps: passing the glucosamine sulfate sodium chloride complex salt through a 40-50 mesh sieve, and then uniformly mixing with the required amount of diluent and wetting agent.

11. The composition of claim 10, the glucosamine sulfate sodium chloride complex salt and lactose are passed through a 40-50 mesh sieve, respectively, and then uniformly mixed with the required amount of corn starch and talc.

12. The composition of claim 10, the mixing condition is 5-15 revolutions / min*10-30 min.

13. The composition of claim 12, the mixing condition is 10 revolutions / min*20 min.

14. The composition of any one of claims 1-9, the composition is an oral preparation.

15. The composition of claim 14, the composition is any one of a tablet, a capsule, a granule, a pill.

16. The composition according to any one of claims 1-9, wherein the bulk density of the composition is 0.7-0.9 g / ml.

17. The composition according to claim 16, wherein the bulk density of the composition is 0.8-0.86 g / ml.

18. The composition according to any one of claims 1-9, wherein the composition is filled into capsules at a filling speed of 900-1200 capsules / min.

19. The composition according to claim 18, wherein the composition is filled into capsules at a filling speed of 1000-1100 capsules / min.

20. A method for preparing the glucosamine sulfate composition according to any one of claims 1-19, the method comprising the following steps: passing the glucosamine sulfate sodium chloride double salt through a 40-50 mesh sieve, and then uniformly mixing the double salt with the required amount of diluent and wetting agent.

21. The method according to claim 20, wherein the lactose in the composition is passed through a 70-120 mesh sieve.

22. The method according to claim 21, wherein the lactose in the composition is passed through an 85-100 mesh sieve.

23. The method according to claim 20, wherein the glucosamine sulfate sodium chloride double salt and the lactose are passed through a 40-50 mesh sieve, respectively, and then uniformly mixing the double salt and the lactose with the required amount of corn starch and talc.

24. The method according to any one of claims 20-23, wherein the mixing is performed at 5-15 revolutions / min for 10-30 min.

25. The method according to claim 24, wherein the mixing is performed at 10 revolutions / min for 20 min.

26. The method according to any one of claims 20-23, wherein the composition is filled into capsules at a filling speed of 900-1200 capsules / min.

27. The method according to claim 26, wherein the composition is filled into capsules at a filling speed of 1000-1100 capsules / min.

28. Use of the glucosamine sulfate composition according to any one of claims 1-19 or prepared by the method according to any one of claims 20-27 for the preparation of a medicament for preventing and treating primary osteoarthritis or secondary osteoarthritis.

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