Glucosamine sulfate composition as well as preparation method and application thereof

Abstract

The invention relates to a glucosamine sulfate composition, which consists of the following components in percentage by weight: 58.0 to 90.0 percent of glucosamine sulfate sodium chloride double salt, 8.0 to 40.0 percent of diluent and 2.0 to 6.0 percent of lubricant. The components and proportion of the composition are scientifically screened, the prepared composition has the advantages of high stability, good in-batch dissolution and inter-batch dissolution uniformity, high bioavailability and the like, and technical guarantee is provided for effectiveness and safety of clinical medication.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a glucosamine sulfate composition, a preparation method thereof and an application thereof. Background Art

[0002] Osteoarthritis is a common chronic pain disease. The main causes include degenerative lesions of articular cartilage caused by abnormal proteoglycan biosynthesis. Pathological manifestations include chronic pain and loss of mobility. Severe osteoarthritis even affects the quality of life of patients. With the continuous aging of the global population, the prevalence of osteoarthritis is on the rise. The cause of primary osteoarthritis is still unclear. Secondary osteoarthritis is mostly caused by other causes (such as trauma, rheumatoid arthritis, neurological diseases, 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 my country exceeds 46.3%.

[0003] D-glucosamine is a normal component of cartilage matrix polysaccharide chains and synovial fluid glucosamine. It can stimulate chondrocytes to synthesize physiological polymeric proteoglycans (such as polyglucosamine and proteoglycans, etc.), stimulate synovial cells to synthesize hyaluronic acid, and inhibit the activity of enzymes that damage cartilage (such as collagenase and phospholipase A2), and prevent the production of superoxide free radicals in damaged tissues and cells, delay the progression of osteoarthritis, inhibit the activity of lysosomes and have anti-inflammatory effects, can be used to improve joint movement and relieve pain, and is widely used for the prevention and treatment of inflammation of systemic bones and joints (including knee joints, hip joints, spine, shoulder joints, hands and wrists, ankle joints, etc.), and its safety and effectiveness have been widely verified. Glucosamine sulfate capsules are used to prevent and treat primary and secondary osteoarthritis, but they have problems such as dissolution and stability that need to be improved. For this reason, it is urgent to develop drugs that improve dissolution and stability to meet the effectiveness and safety requirements of clinical medication. Summary of the invention

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

[0005]

[0006] In the preferred technical scheme of the present invention, the diluent is selected from any one of lactose, starch, corn starch, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, powdered sugar, 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 methylcellulose, or a combination thereof.

[0007] In a preferred technical solution of the present invention, the lubricant is selected from any one of talc, micro-powder silica gel, colloidal silicon dioxide, aluminum hydroxide, sodium lauryl sulfate or a combination thereof.

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

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

[0010] In the preferred technical solution of the present invention, the composition is composed of 78.50% of glucosamine sulfate sodium chloride double salt, 7.25% of lactose, 11.25% of corn starch and 3.0% of talc powder in weight percentage.

[0011] In the preferred technical solution of the present invention, the composition is composed of 78.50% of glucosamine sulfate sodium chloride double salt, 10% of lactose, 8% of corn starch and 3.5% of talc powder in weight percentage.

[0012] In the preferred technical solution of the present invention, the composition is composed of 78.50% of glucosamine sulfate sodium chloride double salt, 3.5% of lactose, 14.5% of corn starch and 3.5% of talc powder in weight percentage.

[0013] In the preferred technical solution of the present invention, the composition is composed of 78.50% of glucosamine sulfate sodium chloride double salt, 11% of lactose, 8% of corn starch and 2.5% of talc powder in weight percentage.

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

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

[0016] In the preferred technical solution of the present invention, 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 it with the required amount of diluent and wetting agent to obtain the composition.

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

[0018] In the preferred technical solution of the present invention, the mixing conditions are 5-15 rpm*10-30min, preferably 10 rpm*20min.

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

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

[0021] In a preferred technical solution of the present invention, the composition is filled into capsules at a filling speed of 900-1200 capsules / min, preferably 1000-1100 capsules / min.

[0022] The object of the present invention is to provide a method for preparing a glucosamine sulfate composition. The composition consists of 58.0%-90.0% of glucosamine sulfate sodium chloride double salt, 8.0%-40.0% of diluent and 2.0%-6.0% of lubricant in weight percentage. The method comprises the following steps: passing the glucosamine sulfate sodium chloride double salt through a 40-50 mesh sieve, and then uniformly mixing it with the required amount of diluent and wetting agent to obtain the composition.

[0023] In the preferred technical scheme of the present invention, the diluent is selected from any one of lactose, starch, corn starch, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, powdered sugar, 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 methylcellulose, or a combination thereof.

[0024] In a preferred technical solution of the present invention, the lubricant is selected from any one of talc, micro-powder silica gel, colloidal silicon dioxide, aluminum hydroxide, sodium lauryl sulfate or a combination thereof.

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

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

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

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

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

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

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

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

[0033] In the preferred technical scheme of the present invention, glucosamine sulfate sodium chloride double salt and lactose are respectively passed through a 40-50 mesh sieve, and then uniformly mixed with the required amount of corn starch and talcum powder to obtain the product.

[0034] In the preferred technical solution of the present invention, the mixing conditions are 5-15 rpm*10-30min, preferably 10 rpm*20min.

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

[0036] In the preferred technical solution 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 technical solution of the present invention, the composition is filled into capsules at a filling speed of 900-1200 capsules / min, preferably 1000-1100 capsules / min.

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

[0039] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[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 ratios of the composition, and the obtained composition has the advantages of high stability, good dissolution uniformity within and between batches, and high bioavailability, which provides technical guarantee for the effectiveness and safety of clinical medication.

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

[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 DESCRIPTION

[0044] The details of the present invention are further explained and described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

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

[0046] The composition of the composition is:

[0047]

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

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

[0050] (2) Weigh the required amount of glucosamine sulfate sodium chloride complex salt, lactose, corn starch and talcum powder, 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 product.

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

[0052] The composition of the composition is:

[0053]

[0054]

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

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

[0057] (2) Weigh the required amount of glucosamine sulfate sodium chloride complex salt, lactose, corn starch and talcum powder, 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, to obtain the product.

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

[0059] The composition of the composition is:

[0060]

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

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

[0063] (2) Weigh the required amounts of glucosamine sulfate sodium chloride complex salt, lactose, corn starch and talcum powder, 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, to obtain the product.

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

[0065] The composition of the composition is:

[0066]

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

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

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

[0070] Comparative Example 1 Preparation of glucosamine sulfate composition

[0071] The composition of the composition is:

[0072]

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

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

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

[0076] Test Example 1 Study on the dissolution rate of the glucosamine sulfate composition of the present invention

[0077] The solubility of the glucosamine sulfate composition of the present invention was investigated with reference to the "Technical Guidelines for Dissolution Tests of Ordinary Oral Solid Preparations" and the "Guidelines for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Preparations".

[0078] The glucosamine sulfate compositions of Example 1 and Comparative Example 1 were taken respectively, and placed under accelerated test conditions (40°C ± 2°C / 75% RH ± 5% RH) for 6 months, and samples were taken at the end of 0 days, 3 months, and 6 months, respectively, using a paddle method (with a sinker) at 50 rpm, a medium volume of 900 ml, and HPLC (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512), a detection wavelength of 344 nm, and the dissolution in four dissolution media (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer and water) was investigated. The results are shown in Tables 1-2.

[0079] Table 1 Example 1 Dissolution Study of Glucosamine Sulfate Composition

[0080]

[0081]

[0082] Table 2 Comparative Example 1 Dissolution Test of Glucosamine Sulfate Composition

[0083]

[0084]

[0085] The glucosamine sulfate composition of Example 1 was placed under accelerated conditions for 6 months, and the dissolution rate was slightly reduced, and the dissolution amount at 15 minutes was greater than 85%, which was a rapid dissolution. The glucosamine sulfate composition of Comparative Example 1 was placed under accelerated conditions for 6 months, and the dissolution rate was significantly reduced, and the maximum dissolution could not be reached at 45 minutes.

[0086] Test Example 2 Study on the dissolution rate of the glucosamine sulfate composition of the present invention

[0087] The glucosamine sulfate compositions of Examples 2-4 were taken respectively, and the paddle method (with sinker) was used at 50 rpm, the medium volume was 900 ml, the sampling time was 5 min, 10 min, and 30 min, and the HPLC method was used for detection (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512), and the detection wavelength was 344 nm. The dissolution curves of the glucosamine sulfate compositions of Examples 2-4 in the dissolution medium (0.1 mol / L hydrochloric acid solution) were investigated, and the results are shown in Table 3. The dissolution amount of the glucosamine sulfate compositions of Examples 2-4 within 10 min was more than 85%.

[0088] Table 3

[0089]

[0090] Test Example 3 Investigation on the dissolution and stability 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 test conditions (40°C ± 2°C / 75% RH ± 5% RH) for 6 months, and the glucosamine sulfate composition of Example 1 was sampled at the end of 0 day, 1 month, 2 months, 3 months, and 6 months, respectively, and the glucosamine sulfate composition of Comparative Example 1 was sampled at 0 day, 3 months, and 6 months, respectively, and the solubility in water was detected according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method), and the related substances were detected according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512). The results are shown in Tables 4-5.

[0092] Table 4 Dissolution and stability test results of glucosamine sulfate composition in Example 1

[0093]

[0094] Table 5 Dissolution and stability test results of the glucosamine sulfate composition of Comparative Example 1

[0095]

[0096] The glucosamine sulfate composition of Comparative Example 1 was placed under accelerated conditions for 6 months, and the detection amounts of related substances (fructosazine, 2,5-deoxyfructosazine) and total impurities increased significantly, and the solubility decreased significantly, both exceeding the limit requirements. The glucosamine sulfate composition of the present invention has excellent solubility and stability.

[0097] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. 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, which consists of 58.0%-90.0% of glucosamine sulfate sodium chloride double salt, 8.0%-40.0% of diluent and 2.0%-6.0% of lubricant in weight percentage.

2. The composition of claim 1, wherein the diluent is selected from any one of lactose, starch, corn starch, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, powdered sugar, 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 methylcellulose or a combination thereof.

3. The composition according to any one of claims 1 to 2, wherein the lubricant is selected from any one of talc, micropowdered silica gel, colloidal silicon dioxide, aluminum hydroxide, sodium lauryl sulfate or a combination thereof.

4. The composition according to any one of claims 1 to 3, wherein the composition consists, by weight percentage, of 58.0%-90.0% glucosamine sulfate sodium chloride double salt, 3.0%-15.0% lactose, 5.0%-25.0% corn starch and 2.0%-6.0% talc.

5. The composition according to any one of claims 1 to 4, wherein the composition consists of 70.0% to 85.0% of glucosamine sulfate sodium chloride double salt, 3.5% to 11.0% of lactose, 6.25% to 16.25% of corn starch and 2.50% to 3.50% of talc, in weight percentage.

6. The composition according to any one of claims 1 to 5, wherein the composition consists, by weight percentage, of 78.50% of glucosamine sulfate sodium chloride double salt, 7.25% of lactose, 11.25% of corn starch and 3.0% of talc.

7. The composition according to any one of claims 1 to 5, wherein the composition consists, by weight percentage, of 78.50% of glucosamine sulfate sodium chloride double salt, 10% of lactose, 8% of corn starch and 3.5% of talc.

8. A composition as described in any one of claims 1 to 7, wherein the particle size distribution of the glucosamine sulfate sodium chloride double salt in the composition is, D10 = 60-85 μm, D50 = 130-170 μm, D90 = 330-380 μm, preferably D10 = 75 μm, D50 = 150 μm, D90 = 355 μm.

9. A method for preparing the composition according to any one of claims 1 to 8, comprising the following steps: passing glucosamine sulfate sodium chloride double salt through a 40-50 mesh sieve, and then uniformly mixing with a required amount of a diluent and a wetting agent to obtain the composition.

10. Use of the glucosamine sulfate composition according to any one of claims 1 to 8 in preparing a medicament for preventing and treating primary osteoarthritis or secondary osteoarthritis.

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