Capsule containing low-hygroscopicity glucosamine sulfate compound and preparation process thereof

Abstract

The invention discloses a capsule containing a glucosamine sulfate compound with low hygroscopicity and a preparation process of the capsule, the content of the capsule is composed of the glucosamine sulfate compound, a lubricant and a disintegrating agent, and an adopted capsule shell is a plant capsule with a certain proportion of surfactant; the glucosamine sulfate compound has the characteristics of low hygroscopicity, high purity and high solubility, and is prepared by compounding glucosamine sulfate, a water-soluble film-forming material and a plasticizer and then performing spray drying. Wherein the glucosamine sulfate accounts for more than 90% of the total weight, the water-soluble film-forming material accounts for 5-10%, and the plasticizer accounts for 1-5%. Various quality indexes and stability of the prepared glucosamine sulfate compound capsule are superior to those of an existing product, the safety and effectiveness of the medicine are improved, and the preparation process of the glucosamine sulfate compound capsule is more suitable for industrial production.

Description

Technical Field

[0001] This product relates to a capsule containing a low hygroscopic glucosamine sulfate complex and its preparation process, belonging to the field of pharmaceutical technology. Background Art

[0002] As the first clinically proven drug for improving osteoarthritis, glucosamine sulfate has been used clinically for more than 20 years, and its efficacy and safety have been recognized by the market. However, due to its high water absorption, the stability of its preparations has always faced challenges. Existing marketed products all use glucosamine sulfate to form a double salt with sodium chloride (potassium chloride), which is not easy to absorb water under normal conditions, but when the humidity exceeds 40%, they still have rapid hygroscopicity. There is a certain lag in absorption in the body, and patients with special poor gastric function may not absorb completely. Moreover, when filled with gelatin capsules, the water in the gelatin capsules is easily reversely absorbed by glucosamine sulfate during the stability process, resulting in slower disintegration and increased impurities. As a result, it is difficult to digest and absorb, affecting the efficacy and safety. At the same time, because of the use of the double salt form, a large amount of inorganic salt substances are introduced, increasing the burden on the liver, kidneys, and heart of the human body, and greatly increasing the risk of taking for patients with hypertension and heart and kidney insufficiency.

[0003] Patent CN117205228A proposed to wrap with an oily substance to form a liposome solution, which is dried and then filled into soft capsules. This changes the active properties of glucosamine sulfate itself, and the clinical use effect is unknown, and the hygroscopicity problem has not been solved either.

[0004] In summary, solving the problems of hygroscopicity without changing the activity of glucosamine sulfate itself, the content of inorganic salts, and improving the stability of the product has very important clinical significance. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a glucosamine sulfate complex capsule with low hygroscopicity, high purity, and high solubility and its preparation process. The present invention uses glucosamine sulfate, a water-soluble film-forming material, and a plasticizer to be compounded, then spray-dried, and filled into plant capsules containing a certain proportion of surfactant. The prepared product has higher purity, better stability, fast dissolution and absorption, definite efficacy, and better safety. It can be better applied to the treatment of osteoarthritis.

[0006] On the one hand, the present invention provides a method for preparing a glucosamine sulfate complex capsule with low hygroscopicity, high purity and high solubility. The capsule preparation process is to add glucosamine sulfate and a water-soluble film-forming material in a specified proportion to more than 4 times the amount of water, fully stir and dissolve, then stir for more than half an hour, add an appropriate amount of plasticizer, stir for 10 - 20 minutes, heat to above 40 degrees, spray dry to obtain uniformly sized particles, sieve, add an appropriate amount of lubricant and disintegrant, and mix and fill into a vegetable capsule shell. Among them, each capsule contains 0.25 g of glucosamine sulfate.

[0007] Furthermore, the dew point temperature of the capsule spray drying is controlled below 30 degrees, and the obtained particle size should be between 80 - 240 um. Preferably, the dew point temperature is 25 - 30 degrees, and the particle size is 130 - 180 um.

[0008] On the one hand, the present invention provides a scheme for a capsule containing a low hygroscopic glucosamine sulfate complex. The capsule is composed of a vegetable capsule shell, a glucosamine sulfate complex, a lubricant and a disintegrant. The glucosamine sulfate complex is obtained by compounding glucosamine sulfate, a water-soluble film-forming material and a plasticizer, and then spray drying. Among them, each capsule contains 0.25 g of glucosamine sulfate.

[0009] Preferably, the vegetable capsule shell contains a certain proportion of surfactant, and the surfactant proportion is 0.5% - 5%. The surfactant is a commonly used surfactant, preferably sodium dodecyl sulfate and Tween - 80. Its main component is vegetable cellulose or water-soluble polysaccharide, preferably a vegetable capsule made of vegetable cellulose, and particularly preferably a vegetable capsule composed of hydroxypropyl methylcellulose.

[0010] The glucosamine sulfate complex is preferably obtained by compounding glucosamine sulfate, a water-soluble film-forming material and a plasticizer, and then spray drying. Among them, glucosamine sulfate accounts for more than 90% of the total weight, the water-soluble film-forming material accounts for 5 - 10%, and the plasticizer accounts for 1 - 5%. The water-soluble film-forming material is preferably a high molecular material such as hydroxypropyl cellulose, polyvinyl alcohol, water-soluble chitin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc. The plasticizer is preferably a water-soluble plasticizer such as glycerol, polyethylene glycol, triacetin, etc.

[0011] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The glucosamine sulfate complex prepared by the present invention has low hygroscopicity, does not absorb moisture during the stability storage process, and there is no tendency for impurities to increase.

[0012] 2. The capsule shell produced by the present invention utilizes a plant-based capsule containing a certain proportion of surfactant, further isolating the glucosamine sulfate complex from the external environment, reducing the potential for moisture absorption and thus ensuring product stability. Plant-based capsules inherently have a low water content and are not susceptible to reverse water absorption like gelatin capsules. The addition of a certain amount of surfactant ensures rapid disintegration and dissolution in the stomach, leading to rapid absorption.

[0013] 3. The capsules prepared by the present invention have an extremely low inorganic salt content, making the product purer. They reduce the burden on the liver, kidneys, and heart, and are also suitable for patients with hypertension and heart and kidney dysfunction. DETAILED DESCRIPTION

[0014] The experimental methods in the following examples of the present invention, where specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0015] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0016] The terms "comprise," "comprising," and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, product, or device comprising a series of steps is not limited to the listed steps or modules but may optionally include steps not listed, or other steps inherent to the process, method, product, or device.

[0017] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be described in further detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention. The following examples further describe the present invention, but these examples are not intended to limit the scope of the present invention.

[0018] Example 1 Preparation of glucosamine sulfate complex The specific process steps are as follows: glucosamine sulfate and a water-soluble film-forming material are added to water in a prescribed ratio, which is four times the amount, and the mixture is thoroughly stirred and dissolved. The mixture is then stirred for at least half an hour. An appropriate amount of plasticizer is added and stirred for 10-20 minutes. The mixture is heated to above 40°C, spray-dried at a dew point of 30%, and uniformly sized particles are obtained. The hygroscopicity of the particles is then measured. The specific mass ratios of glucosamine sulfate, water-soluble film-forming material, and plasticizer in this example are shown in Table 1.

[0019] Hygroscopicity Determination Method Take 10 g of glucosamine sulfate complex or the content of the original research glucosamine sulfate compound of Rhodia, accurately weigh, place them in a weighing bottle dried to constant weight at 105 °C respectively, number them, put them in a stability test chamber at a temperature of 25 °C ± 2 °C and a humidity of 50% ± 10%, place for 8 hours, take out, and accurately weigh. Calculate the ratio of the increased weight to the weight of the original sample, which is the hygroscopic percentage. Repeat three times, take the median value, and RSD ≤ 2%.

[0020] Table 1 Comparison of Results of Different Mass Ratios of Glucosamine Sulfate, Water-Soluble Film-Forming Material, and Plasticizer Number Mass ratio of active ingredient Mass ratio of water-soluble film-forming material Mass ratio of plasticizer Moisture absorption percentage 1 Glucosamine sulfate 94% Hydroxypropyl cellulose 5% Polyethylene glycol 1% 4.2% 2 Glucosamine sulfate 94% Hydroxypropyl cellulose 10% Polyethylene glycol 1% 2.5% 3 Glucosamine sulfate 90% Hydroxypropyl cellulose 5% Polyethylene glycol 5% 4.0% 4 Glucosamine sulfate 91% Hydroxypropyl cellulose 8% Polyethylene glycol 1% 2.6% 5 Glucosamine sulfate 90% Hydroxypropyl cellulose 8% Polyethylene glycol 2% 2.5% 6 Glucosamine sulfate 91% Polyvinyl alcohol 8% Glycerol 1% 2.8% 7 Glucosamine sulfate 91% Polyvinyl alcohol 8% Polyethylene glycol 1% 2.9% 8 Glucosamine sulfate 91% Hydroxypropyl cellulose 8% Triacetin 1% 3.2% 9 Glucosamine sulfate 91% Water-soluble chitin 8% Polyethylene glycol 1% 4.5% 10 Glucosamine sulfate 91% Hydroxypropyl methylcellulose 8% Polyethylene glycol 1% 2.7% 11 Glucosamine sulfate 91% Polyvinylpyrrolidone 8% Polyethylene glycol 1% 3.1% 12 Content of original Roche —— —— 5.5% Note: The total of glucosamine sulfate, water-soluble film-forming material, and plasticizer is 100 g.

[0021] The results show that the hygroscopicity of the glucosamine sulfate complex prepared according to Example 1 is better than that of the content of the original research glucosamine sulfate compound of Rhodia.

[0022] Example 2 Preparation of Glucosamine Sulfate Complex The specific process steps are as follows: Add 91 g of glucosamine sulfate and 8 g of hydroxypropyl cellulose to 400 ml of water, stir well to dissolve, then stir for more than half an hour, add 1 g of polyethylene glycol, stir for 10 - 20 minutes, heat to above 40 °C (heating temperature), control the spray rate and inlet air temperature, and control the dew point at 25 - 50% for spray drying to obtain particles with uniform size, and measure the particle size and angle of repose of the finished product. In this example, the heating temperature, spray rate, inlet air temperature conditions, and the obtained particle size and angle of repose of the finished product are shown in Table 2 for specific conditions and results.

[0023] Table 2 Different Spray Drying Conditions (Heating Temperature, Spray Rate, Atomization Temperature) The results show that the particle size of the glucosamine sulfate complex prepared according to Example 2 is between 90 - 220, and the angle of repose is between 26.2 - 57.2, which can meet the requirements of direct filling and is suitable for industrial production.

[0024] Put 10 g of each of the glucosamine sulfate complex particles obtained in Example 2 into 10 ml of water at 25 °C ± 2 °C and 10 ml of dilute hydrochloric acid at 37 °C ± 2 °C respectively, record the dissolution time and dissolution phenomenon, and the results are shown in Table 3.

[0025] Take 50 g of the glucosamine sulfate complex granules obtained in Example 2, and add 0.2 g of silicon dioxide and 0.5 g of sodium carboxymethyl starch respectively. Determine the moisture content of the complex and the moisture content of the blank gelatin capsule shell. Fill the remaining complex into gelatin capsules and place them in PVC bottles. Accelerate the placement at 40°C ± 2°C and 75% ± 5% for 6 months, and determine the moisture content and related substances of the capsule content and the capsule shell. The results are shown in Table 3.

[0026] Test method for related substances Take an appropriate amount of the fine powder of this product (equivalent to about 500 mg of glucosamine sulfate), weigh it accurately, place it in a 50 ml volumetric flask, add an appropriate amount of acetonitrile-water (1:1), shake to dissolve and dilute to the mark, shake well, filter, and take the subsequent filtrate as the test solution; accurately measure 2 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with acetonitrile-water (1:1), shake well, and use it as the control solution. Take appropriate amounts of N-acetylglucosamine and glucosamine hydrochloride system suitability reference substances, weigh them accurately, dissolve and dilute with acetonitrile-water (1:1) to prepare a solution containing about 10 μg of N-acetylglucosamine and about 10 mg of glucosamine hydrochloride per 1 ml as the system suitability solution. According to the following chromatographic conditions, chromatographic column: Titank HILIC 5μ 250*4.6mm (product number: FMG-5568-EONU), flow rate: 1.0 mL / min; column temperature: 35°C; detector: UV 195nm; mobile phase: acetonitrile-20 mM dipotassium hydrogen phosphate (pH 7.5) = (70:30). Accurately measure 10 μl of the system suitability solution and inject it into the liquid chromatograph, record the chromatogram. Except for the blank solvent peak and the chloride ion peak, N-acetylglucosamine, 2,5-deoxyfructosazine, fructosazine, and glucosamine sulfate elute in sequence, and the resolution between each peak is not less than 1.5. Accurately measure 10 μl of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity to make the peak height of the main component chromatographic peak about 20% of the full scale. Then accurately measure 10 μl of the test solution and the control solution respectively, inject them into the liquid chromatograph, and record the chromatogram until 3 times the retention time of the main component peak.

[0027] Table 3-1 Comparison of the data of the sample in Example 2 and the original research product of Rhodia Number Dissolution time (10 ml of water at 25°C ± 2°C) Dissolution phenomenon (10 ml of water at 25°C ± 2°C) Dissolution time (10 ml of dilute hydrochloric acid at 37°C ± 2°C) Dissolution phenomenon (10 ml of dilute hydrochloric acid at 37°C ± 2°C) Moisture content at 0 month Moisture content of blank capsule shell at 0 month 1 8.1 min Completely dissolved 3.3 min Completely dissolved 0.42% 10.3% 2 15.5 min Completely dissolved 7.1 min Completely dissolved 0.45% 10.3% 3 10.4 min Completely dissolved 4.2 min Completely dissolved 0.52% 10.3% 4 11.9 min Completely dissolved 4.7 min Completely dissolved 0.37% 10.3% 5 9.2 min Completely dissolved 3.5 min Completely dissolved 0.54% 10.3% 6 9.6 min Completely dissolved 3.7 min Completely dissolved 0.37% 10.3% 7 10.1 min Completely dissolved 3.6 min Completely dissolved 0.42% 10.3% 8 11.1 min Completely dissolved 4.2 min Completely dissolved 0.44% 10.3% 9 9.3 min Completely dissolved 3.3 min Completely dissolved 0.38% 10.3% 10 5.5 min Completely dissolved 2.6 min Completely dissolved 0.39% 10.3% Roche 14.8 min A small amount of the main drug was not dissolved 8.6 min A small amount of the main drug was not dissolved 0.71% 9.6% . Table 3-2 Comparison of the data of the sample in Example 2 and the original research product of Rhodia Number Maximum single impurity % (related substances at 0 month) Total impurity % (related substances at 0 month) Maximum single impurity % (related substances at 6 months) Total impurity % maximum single impurity % (related substances at 6 months) Moisture content at 6 months Moisture content of blank capsule shell at 6 months 1 0.05% 0.13% 0.07% 0.18% 0.92% 9.2% 2 0.05% 0.14% 0.06% 0.17% 0.85% 9.4% 3 0.04% 0.12% 0.05% 0.19% 0.87% 9.6% 4 0.05% 0.15% 0.05% 0.16% 0.77% 9.4% 5 0.04% 0.13% 0.04% 0.15% 0.74% 9.3% 6 0.03% 0.14% 0.06% 0.17% 0.77% 9.9% 7 0.05% 0.15% 0.05% 0.15% 0.88% 9.1% 8 0.04% 0.13% 0.04% 0.16% 0.94% 9.1% 9 0.03% 0.14% 0.05% 0.18% 0.95% 9.7% 10 0.05% 0.15% 0.07% 0.21% 0.96% 9.5% Roche 0.09% 0.23% 0.16% 0.43% 2.71% 7.3% The capsule shell became brittle The results show that the glucosamine sulfate complex prepared according to Example 2 dissolves more thoroughly, faster, and has better stability in water and dilute hydrochloric acid (simulating gastric juice). After accelerating the placement for 6 months, compared with the original research product, the sample prepared in Example 2 absorbs less reverse moisture from the capsule shell by the content.

[0028] Example 3 Comparison of the Quality of Different Capsules of Glucosamine Sulfate Complex The specific implementation is as follows: Prepare the glucosamine sulfate complex according to the method of No. 7 in Example 2. Take 200 g of this complex and add 0.8 g of magnesium stearate and 2.5 g of croscarmellose sodium respectively. Fill them into gelatin capsules, 0.5%-sodium lauryl sulfate hydroxypropyl methylcellulose capsules, 0.5%-Tween-80 hydroxypropyl methylcellulose capsules, 1.0%-sodium lauryl sulfate hydroxypropyl methylcellulose capsules, 1.0%-Tween-80 hydroxypropyl methylcellulose capsules, and 5%-sodium lauryl sulfate hydroxypropyl methylcellulose capsules respectively. Compare the dissolution degrees of the glucosamine sulfate complex under different capsule shells. After accelerating the placement at 40°C ± 2°C and 75% ± 5% for 6 months, measure the dissolution degree, the moisture content of the capsule content, and the related substances. The results are shown in Table 4.

[0029] Table 4 Comparison of the Quality of Different Capsule Shells Number Capsule ingredients Dissolution percentage (at 0 month) Dissolution percentage (accelerated for 6 months) Maximum single impurity % (accelerated for 6 months) Total impurity % (accelerated for 6 months) Moisture percentage (accelerated for 6 months) 1 Gelatin capsule 100.5% 87.2% 0.04% 0.18% 0.74% 2 0.5% - Sodium dodecyl sulfate hydroxypropyl methylcellulose capsule 100.7% 98.7% 0.04% 0.11% 0.44% 3 0.5% - Tween-80 hydroxypropyl methylcellulose capsule 101.4% 96.9% 0.03% 0.12% 0.35% 4 1.0% - Sodium dodecyl sulfate hydroxypropyl methylcellulose capsule 100.3% 99.7% 0.04% 0.13% 0.38% 5 1.0% - Tween-80 hydroxypropyl methylcellulose capsule 99. 9% 101.2% 0.03% 0.12% 0.41% 6 5% - Sodium dodecyl sulfate hydroxypropyl methylcellulose capsule 101.1% 100.3% 0.04% 0.11% 0.39% The results show that for the products prepared with different capsule shells in Example 3, the quality of the glucosamine sulfate complex capsules using plant capsules is significantly better than that of gelatin capsules.

Claims

1. A capsule containing a low-hygroscopic glucosamine sulfate complex, characterized by: It consists of a plant capsule shell, a glucosamine sulfate complex, a lubricant and a disintegrant; the glucosamine sulfate complex is formed by compounding glucosamine sulfate, a water-soluble film-forming material and a plasticizer and then spray-drying; each capsule contains 0.25g of glucosamine sulfate.

2. The plant capsule shell according to claim 1, comprising a surfactant in a certain proportion.

3. The plant capsule shell according to claim 1, wherein the surfactant ratio is 0.5%-5%; the surfactant is a commonly used surfactant, preferably sodium lauryl sulfate or Tween-80.

4. The plant capsule shell according to claim 1, wherein the main component is plant cellulose or water-soluble polysaccharide, preferably a plant cellulose plant capsule, particularly preferably a plant capsule composed of hypromellose.

5. The glucosamine sulfate complex according to claim 1 is prepared by compounding glucosamine sulfate, a water-soluble film-forming material, and a plasticizer, followed by spray drying; wherein the glucosamine sulfate accounts for more than 90% of the total weight, the water-soluble film-forming material accounts for 5-10%, and the plasticizer accounts for 1-5%.

6. The water-soluble film-forming material according to claim 5 is a polymer material such as hydroxypropyl cellulose, polyvinyl alcohol, water-soluble chitin, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, etc.

7. The plasticizer according to claim 6 is a water-soluble plasticizer such as glycerol, polyethylene glycol, or triacetin.

8. The capsule preparation process according to claim 1 comprises adding glucosamine sulfate and a water-soluble film-forming material in a prescribed proportion to water in an amount of 4 times or more, stirring and dissolving the mixture, stirring for more than half an hour, adding an appropriate amount of plasticizer, stirring for 10-20 minutes, heating to above 40 degrees, spray drying to obtain particles of uniform size, sieving, adding an appropriate amount of lubricant and disintegrant, and then mixing and filling the mixture into a plant capsule shell; wherein, Each capsule contains 0.25g of glucosamine sulfate.

9. The capsule spray drying method according to claim 8 has a dew point temperature controlled below 30 degrees Celsius, and the particle size of the obtained particles should be 80-240 μm; preferably, the dew point temperature is 25-30 degrees Celsius, and the particle size is 130-180 μm.

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