A Calcitonin Tablet and Its Preparation Method

Abstract

This application relates to the field of biopharmaceutical technology. Specifically, it relates to a calcitonin tablet and a preparation method thereof. Among them, the calcitonin tablet, by weight, comprises components: 20-30 parts of a drug main body, 50-80 parts of a filler, 5-15 parts of a disintegrant, and 0.5-2 parts of a lubricant. The drug main body comprises 5-12 parts of salmon calcitonin liposome, 8-18 parts of a protective agent, and 1-2 parts of complex A. Among them, complex A comprises lactose, D-mannitol, and glycine. By adopting the above technical solution, by adding complex A to the components, the disintegration speed of the drug can be increased, especially the disintegration speed in a less aqueous environment. On the one hand, it can improve the taste of taking medicine for patients, and on the other hand, it can also help improve the bioavailability of the drug.

Description

Technical Field

[0001] This application relates to the technical field of biopharmaceuticals, and specifically, to a calcitonin tablet and a preparation method thereof. Background Art

[0002] Osteoporosis is a disease characterized by reduced bone mass throughout the body, decreased bone strength, increased bone fragility, and a tendency to fracture easily. With the continuous aging of the world's population, osteoporosis will become a large-scale global health problem. Currently, typical treatment drugs mainly focus on bone resorption inhibitors, among which calcitonin products account for more than half of the market.

[0003] Since the discovery of salmon calcitonin in the 1970s, it has been widely used in the treatment of osteoporosis. In the prior art, common dosage forms of salmon calcitonin include injection and nasal spray. The treatment cycle of osteoporosis is relatively long. After intramuscular or subcutaneous injection, the blood concentration reaches its peak in about 0.5 - 1 hour, and the half-life is about 10 minutes. Therefore, for the prevention and treatment of osteoporosis and other diseases, long-term and frequent injection administration is required, and the patient compliance is poor; the nasal spray is a non-invasive dosage form that is easily accepted by patients, but due to the barrier effect of the nasal mucosa, its absolute bioavailability is relatively low.

[0004] Although oral formulations of calcitonin have been proposed, such as the invention patent application with the publication number CN107952063A and the invention patent with the publication number CN101569608B, there is still room for improvement in their bioavailability in the body.

[0005] In view of this, the present application is proposed. Summary of the Invention

[0006] The purpose of the present application is to provide a calcitonin tablet and a preparation method thereof to solve at least one of the technical problems described in the background art.

[0007] Specifically, in the first aspect of the present application, a calcitonin tablet is provided, which, by weight, comprises the following components:

[0008] 20 - 30 parts of the drug main body,

[0009] 50 - 80 parts of a filler,

[0010] 5 - 15 parts of a disintegrant,

[0011] 0.5 - 2 parts of a lubricant,

[0012] The drug main body comprises 5 - 12 parts of salmon calcitonin liposome, 8 - 18 parts of a protective agent, and 1 - 2 parts of complex A, wherein the complex A comprises lactose, D-mannitol, and glycine.

[0013] By adopting the above technical solution, adding complex A to the components can improve the disintegration rate of the drug, especially the disintegration rate in a less aqueous environment. On the one hand, it can improve the taste of taking medicine for patients, and on the other hand, it can also help improve the bioavailability of the drug.

[0014] Preferably, the protective agent includes chitin and polyethylene glycol 4000, and the weight ratio of the two is 1-2:1.

[0015] Preferably, the weight ratio of the lactose, D-mannitol, and glycine is 2-4:5-8:1.

[0016] Preferably, the calcitonin tablet, by weight, includes components:

[0017] 24 parts of the drug main body,

[0018] 65 parts of the filler,

[0019] 10 parts of the disintegrant,

[0020] 1 part of the lubricant,

[0021] The drug main body includes 8 parts of salmon calcitonin liposome, 14 parts of the protective agent, and 2 parts of complex A. Among them, the complex A includes 0.6 part of lactose, 1.2 parts of D-mannitol, and 0.2 part of glycine.

[0022] Preferably, the preparation method of the salmon calcitonin liposome includes the steps:

[0023] Mix phosphatidylcholine, sodium cholate, and cholesterol in a weight ratio of 4-6:0.1-0.5:1 to form complex B. Mix chloroform and methanol in a ratio of 0.5-2:1 to form solution A. Evaporate to remove the organic solvent to obtain flexible liposomes;

[0024] Dissolve salmon calcitonin in a phosphate buffer solution with a pH of 6-8 to form a salmon calcitonin solution. Add liposomes in a mass ratio of liposomes to salmon calcitonin of 8-12:1, hydrate for 1-2 hours, and then ultrasonically oscillate for 20-40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension.

[0025] Preferably, the evaporation is rotary evaporation.

[0026] Preferably, dissolve the salmon calcitonin in a phosphate buffer solution with a pH of 7.0.

[0027] Preferably, add liposomes in a mass ratio of liposomes to salmon calcitonin of 10:1, hydrate for 90 min, and then ultrasonically oscillate for 30 min.

[0028] Preferably, the preparation method of complex A includes:

[0029] Dissolve D-mannitol at 40%-60% of the labeled amount in an appropriate amount of water to obtain a mannitol solution.

[0030] Take lactose, glycine, and the remaining D-mannitol and place them in a fluidized bed.

[0031] Use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed.

[0032] After spraying, dry at 55-60°C for 30-60 minutes to obtain complex A particles.

[0033] Screen complex A with a particle size of 180-250 μm.

[0034] Preferably, in the step of spraying with the mannitol solution as a granulating agent, the pump flow rate is 10-30 L / h.

[0035] Preferably, during the granulation process, the inlet air temperature of the fluidized bed is 45-60°C, the inlet air volume is 15-20 m 3 / h, and the atomization pressure is 0.5-1.0 Bar.

[0036] Preferably, during the granulation process, the temperature of the materials does not exceed 50°C, preferably 30-40°C.

[0037] Preferably, the concentration of the mannitol solution is 10-15% (i.e., 10-15 g of mannitol is dissolved in 100 ml of water).

[0038] Preferably, after drying, the water content of the complex A particles does not exceed 8%, preferably 4-6%.

[0039] Preferably, the disintegration time of the calcitonin tablets is 20-60 s.

[0040] Preferably, the filler is one or a combination of several of starch, dextrin, microcrystalline cellulose, lactose, and pregelatinized starch.

[0041] Preferably, the disintegrant is one or a combination of several of crospovidone, sodium carboxymethyl starch, sodium cross-linked carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose sodium.

[0042] Preferably, the lubricant is one or a combination of several of magnesium stearate, colloidal silica, and talc powder.

[0043] Preferably, the complex A does not contain glucose and sucrose.

[0044] In the second aspect of the present application, there is provided a method for preparing the calcitonin tablets as described in the first aspect, including the steps:

[0045] Prepare salmon calcitonin liposomes from the labeled amount of salmon calcitonin, and the salmon calcitonin liposomes are in suspension form;

[0046] Prepare complex A in a fluidized bed;

[0047] Add the labeled amounts of chitin and polyethylene glycol 4000 to the salmon calcitonin liposomes, mix and then perform spray drying to obtain powder C. After mixing the powder C with complex A, press tablets to obtain calcitonin tablets.

[0048] Preferably, the preparation of salmon calcitonin liposomes from the labeled amount of salmon calcitonin includes the steps of:

[0049] Mix phosphatidylcholine, sodium cholate, and cholesterol in a weight ratio of 4 - 6:0.1 - 0.5:1 to form complex B. Mix chloroform and methanol in a ratio of 0.5 - 2:1 to form solution A, and evaporate to remove the organic solvent to obtain flexible liposomes;

[0050] Dissolve salmon calcitonin in a phosphate buffer solution with a pH of 6 - 8 to form a salmon calcitonin solution. Add liposomes in a mass ratio of liposomes to salmon calcitonin of 8 - 12:1, hydrate for 1 - 2 hours, and then ultrasonically oscillate for 20 - 40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are in suspension form.

[0051] Preferably, the preparation of complex A in a fluidized bed includes the steps of:

[0052] Dissolve 40% - 60% of the labeled amount of D - mannitol in an appropriate amount of water to prepare a mannitol solution,

[0053] Take lactose, glycine, and the remaining D - mannitol and place them in a fluidized bed,

[0054] Use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed;

[0055] After spraying, dry at 55 - 60 °C for 30 - 60 min to obtain complex A particles,

[0056] Screen complex A with a particle size of 180 - 250 μm.

[0057] Preferably, the evaporation is rotary evaporation.

[0058] Preferably, dissolve the salmon calcitonin in a phosphate buffer solution with a pH of 7.0.

[0059] Preferably, add liposomes in a mass ratio of liposomes to salmon calcitonin of 10:1, hydrate for 90 min, and then ultrasonically oscillate for 30 min.

[0060] Preferably, in the spray step using mannitol solution as a granulating agent, the pump flow rate is 10 - 30 L / h.

[0061] Preferably, during the granulation process, the inlet air temperature of the fluidized bed is 45 - 60 °C, the inlet air volume is 15 - 20 m 3 / h, and the atomization pressure is 0.5 - 1.0 Bar.

[0062] Preferably, during the granulation process, the temperature of the material is not higher than 50 °C, preferably 30 - 40 °C.

[0063] Preferably, the concentration of the mannitol solution is 10 - 15% (i.e., 10 - 15 g of mannitol is dissolved in 100 ml of water).

[0064] Preferably, after drying, the water content of the complex A particles is not higher than 8%, preferably 4 - 6%.

[0065] In summary, the present application has the following beneficial effects:

[0066] 1. For the calcitonin tablets provided in the present application, by adding complex A to the components, the disintegration rate of the drug can be increased, especially the disintegration rate in a low - water environment. On the one hand, it can improve the taste of taking medicine for patients, and on the other hand, it can also help improve the bioavailability of the drug.

[0067] 2. For the calcitonin tablets provided in the present application, by adding chitin and polyethylene glycol 4000 as protective agents, the influence of gastric acid on the activity of calcitonin after taking the medicine can be reduced, and the bioavailability of the drug can be improved.

[0068] 3. For the preparation method of the calcitonin tablets provided in the present application, by preparing salmon calcitonin liposomes and complex A, and mixing the two and then tabletting, tablets with more stable quality and fast disintegration rate can be obtained. While ensuring the product quality, the bioavailability of the drug is higher, and it has good commercial prospects. Description of the Drawings

[0069] Figure 1 is the disintegration rate of experimental schemes A - G in Example 4 of the present application at the 0th day of the accelerated test in a low - water state;

[0070] Figure 2 is the disintegration rate of experimental schemes A - G in Example 4 of the present application at the 6th month of the accelerated test in a low - water state;

[0071] Figure 3 is the disintegration rate of experimental schemes A - G in Example 4 of the present application at the 0th day of the accelerated test in a high - water state;

[0072] Figure 4This is the disintegration rate of experimental schemes A - G in Example 4 of this application under the abundant water condition at the 6th month of the accelerated test;

[0073] Figure 5 This is the ratio of blood calcium concentration in Examples 1 - 9 of this application;

[0074] Figure 6 This is the ratio of blood calcium concentration in Comparative Examples 1 - 9 of this application. Detailed Description of the Invention

[0075] Here, exemplary embodiments will be described in detail, and their examples are shown in the drawings. When the following description refers to the drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with this application. Instead, they are merely examples of devices and methods consistent with some aspects of this application as detailed in the appended claims.

[0076] The terms used in this application are for the sole purpose of describing specific embodiments and are not intended to limit this application. The singular forms "a", "the", and "said" used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term "and / or" used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.

[0077] This application will be described in detail below through examples.

[0078] In the prior art, salmon calcitonin is widely used in the treatment of osteoporosis. However, the common dosage forms of salmon calcitonin include injections and nasal sprays, and the compliance and bioavailability of patients are not good. Although oral preparations of calcitonin have been proposed, there is still room for improvement in their bioavailability in the body. In particular, the applicant has found that osteoporosis patients often have phenomena such as dry mouth. Existing calcitonin tablets have poor disintegration effects in the oral cavity under water - deficient conditions, which affects their absorption in the stomach.

[0079] In view of this, the inventive concept of this application is to provide a calcitonin tablet, which, by weight, includes components: 20 - 30 parts of drug main body, 50 - 80 parts of filler, 5 - 15 parts of disintegrant, 0.5 - 2 parts of lubricant. The drug main body includes 5 - 15 parts of salmon calcitonin liposome, 8 - 18 parts of protective agent, and 1 - 5 parts of complex A, wherein the complex A includes lactose, D - mannitol, and glycine. By adopting the technical solution of this application, by adding complex A to the components, the disintegration speed of the drug can be increased, especially the disintegration speed under less water environment. On the one hand, it can improve the taste of patients taking medicine, and on the other hand, it can also help improve the bioavailability of the drug.

[0080] To better understand the above technical solutions, the above technical solutions will be described in detail below in combination with specific embodiments. Those skilled in the art should also understand that the reaction time and drug feeding involved in this application cannot be absolutely accurate during the actual production process, but are within the allowable error range. For example, if it is desired to heat the sample for 30 minutes, the actual operation may be 1 second more or less than 30 minutes; if it is desired to weigh 30 g of the sample, the actual weight may be 30.001 g or 29.998 g.

[0081] Experimental Example 1 Drop Method Disintegration Test

[0082] The measuring device in this experimental example mainly consists of an iron stand, a sieve, a burette, and a liquid receiving device. Among them, the burette is fixed at a specific position on the iron stand and its height can be adjusted; the liquid receiving device is arranged at the bottom of the iron stand, and the projection of the burette on the bottom surface is located inside the liquid receiving device, so that the liquid receiving device can collect the liquid dropped by the burette; the sieve is located on the liquid receiving device and is used to carry the tablets. The sieve is 40 mesh, and the tablets are located on the moving path of the liquid dropped by the burette, so that the liquid can contact and moisten the tablets.

[0083] The measurement method is as follows: Fill the burette with water at 37 °C, control the water droplet speed to be 0.5 ml / min or 2 ml / min, and the vertical distance between the water droplet and the tablet is 2 cm to prevent the impact on the tablet due to too high a distance. Place the tablet on the sieve so that the water in the burette can just drop onto the tablet, start timing, and record the time from when the tablet dissolves and leaks from the sieve as the disintegration time. The disintegration efficiency of the tablet is tested at 1 min, 2 min, and 3 min respectively, that is, divided into three groups of 1 min, 2 min, and 3 min. Stop titration at the corresponding time, and calculate the weight loss of the tablet after drying, so as to calculate the disintegration efficiency.

[0084] Experimental Example 2 Accelerated Test

[0085] Take the sample and place it for 6 months under the conditions of 40 °C ± 2 °C and RH 75% ± 5%.

[0086] Experimental Example 3 Efficacy Test

[0087] Test method: Take female SD rats with a body weight of 200 ± 20 g, fast overnight the day before yesterday, fast on the day of administration, and allow them to eat 8 hours after administration. Randomly divide the rats into groups of 4 each, and give them calcitonin tablets with different components orally at a dose of 150 IU / kg body weight.

[0088] Detection method: The serum calcium ion concentration was measured using an OCPC o-cresolphthalein complexone kit. Blood was collected from the caudal vein of rats at 0, 1, 2, 4, and 8 h after administration, 0.3 ml each time. The blood samples were centrifuged at 4000 rpm within 30 min to separate the serum. Each blood sample was measured 3 times and the average value was taken. The calcium concentration ratio was calculated, with the serum calcium ion concentration at 0 h as the denominator and the calcium concentration at other time points as the numerator.

[0089] Experimental Example 4

[0090] In this experimental example, the disintegration time of each experimental scheme under the droplet method was tested, and the water droplet speed was controlled at 0.5 ml / min.

[0091] Experimental Scheme A

[0092] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol were mixed in a ratio of 1:1 to form solution A. The organic solvent was evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension.

[0093] The salmon calcitonin liposomes were taken for spray drying to obtain powder C. 8 parts of powder C were taken by weight, mixed evenly with 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and pressed into tablets. The tablet weight was controlled at 500 mg.

[0094] Experimental Scheme B

[0095] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol were mixed in a ratio of 1∶1 to form solution A. The organic solvent was evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 mmin to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension.

[0096] Add chitin in an amount of 7 parts by weight and polyethylene glycol 4000 in an amount of 7 parts by weight to the salmon calcitonin liposome. After mixing, perform spray drying to obtain 22 parts of powder C. Mix the powder C evenly with 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, with the tablet weight controlled at 500 mg.

[0097] Experimental protocol C

[0098] Prepare salmon calcitonin liposome: Mix phosphatidylcholine, sodium cholate, and cholesterol in a ratio of 5:0.2:1 by weight to form complex B. Mix chloroform and methanol in a ratio of 1:1 to form solution A. Evaporate to remove the organic solvent to obtain flexible liposomes. Dissolve salmon calcitonin in a phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Add liposomes in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrate for 1 hour, and then perform ultrasonic oscillation for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension.

[0099] Add chitin in an amount of 7 parts by weight and polyethylene glycol 4000 in an amount of 7 parts by weight to the salmon calcitonin liposome. After mixing, perform spray drying to obtain 22 parts of powder C. Mix the powder C evenly with 1.2 parts of D-mannitol, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, with the tablet weight controlled at 500 mg.

[0100] Experimental protocol D

[0101] Prepare salmon calcitonin liposome: Mix phosphatidylcholine, sodium cholate, and cholesterol in a ratio of 5:0.2:1 by weight to form complex B. Mix chloroform and methanol in a ratio of 1:1 to form solution A. Evaporate to remove the organic solvent to obtain flexible liposomes. Dissolve salmon calcitonin in a phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Add liposomes in a mass ratio of liposomes to salmon calcitonin solution of 10::1, hydrate for 1 hour, and then perform ultrasonic oscillation for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension.

[0102] Add chitin in an amount of 7 parts by weight and polyethylene glycol 4000 in an amount of 7 parts by weight to the salmon calcitonin liposome. After mixing, perform spray drying to obtain 22 parts of powder C. Mix the powder C evenly with 1.2 parts of D-mannitol, 0.6 parts of lactose, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, with the tablet weight controlled at 500 mg.

[0103] Experimental protocol E

[0104] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol are mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol are mixed in a ratio of 1:1 to form solution A. The organic solvents are evaporated to obtain flexible liposomes. Salmon calcitonin is dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes are added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension;

[0105] Chitosan with a weight portion of 7 and polyethylene glycol 4000 with a weight portion of 7 are added to the salmon calcitonin liposomes. After mixing, spray drying is carried out to obtain 22 parts of powder C. Powder C is mixed evenly with 1.2 parts of D-mannitol, 0.6 parts of lactose, 0.2 parts of glycine, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and then tabletted to obtain calcitonin tablets, and the tablet weight is controlled at 500 mg.

[0106] Experimental protocol F

[0107] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol are mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol are mixed in a ratio of 1:1 to form solution A. The organic solvents are evaporated to obtain flexible liposomes. Salmon calcitonin is dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes are added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension;

[0108] 0.6 parts by weight of D-mannitol is dissolved in an appropriate amount of water to prepare a 10% mannitol solution; 0.6 parts of lactose, 0.2 parts of glycine, and the remaining 0.6 parts of D-mannitol are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, drying is carried out at 58 °C for 40 min to obtain complex A particles; complex A with a particle size of 180 - 250 μm is screened; among them, in the step of spraying with the mannitol solution as the granulating agent, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50 °C, the inlet air volume is 16 m 3 / h, and the atomization pressure is 0.8 Bar;

[0109] Add chitin with a weight portion of 7 and polyethylene glycol 4000 with a weight portion of 7 to the salmon calcitonin liposome. After mixing, perform spray drying to obtain 22 parts of powder C. Mix the powder C evenly with 2 parts of complex A, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, with the tablet weight controlled at 500 mg.

[0110] Experimental protocol G

[0111] Prepare salmon calcitonin liposome: Mix phosphatidylcholine, sodium cholate, and cholesterol in a weight ratio of 5:0.2:1 to form complex B. Mix chloroform and methanol in a ratio of 1:1 to form solution A. Evaporate to remove the organic solvent to obtain flexible liposomes. Dissolve salmon calcitonin in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Add liposomes in a mass ratio of liposome to salmon calcitonin solution of 10:1, hydrate for 1 hour, and then ultrasonically oscillate for 30 min to obtain salmon calcitonin liposome, and the salmon calcitonin liposome is a suspension;

[0112] Take 0.6 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to prepare a 10% mannitol solution; take 0.6 parts of lactose, 0.2 parts of glycine, and the remaining 0.6 parts of D-mannitol and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 58 °C for 40 min to obtain complex A particles; screen complex A with a particle size of 180 - 250 μm; among them, in the step of spraying with the mannitol solution as a granulating agent, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50 °C, the inlet air volume is 16 m 3 / h, and the atomization pressure is 0.8 Bar;

[0113] Take the salmon calcitonin liposome and perform spray drying to obtain powder C. Take 8 parts by weight of powder C, mix it evenly with 2 parts of complex A, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, with the tablet weight controlled at 500 mg.

[0114] After subjecting experimental protocols A - G to accelerated testing according to the method of experimental example 2, test the disintegration time according to the method of experimental example 1. Each group of tests includes at least 1000 tablets, and the test data is as Figure 1 - Figure 2 shown, and this data is the average value of sampling and testing 10 tablets.

[0115] From Figure 1 , Figure 2 the experimental results, those skilled in the art can understand:

[0116] First, comparing experimental protocol C with experimental protocols A - B, the disintegration rate of experimental protocol C has been significantly improved. The applicant speculates that this is due to the good water solubility of D - mannitol;

[0117] Second, comparing experimental protocols C - E, the difference is that experimental protocols D and E added lactose and glycine components on the basis of C, but there is no significant difference in the disintegration rates among the three; further, comparing experimental protocol F with experimental protocol E, the components selected by the two are basically the same, but since in experimental protocol F, D - mannitol, lactose, and glycine are prepared into complex A by fluidized bed granulation, it has a better disintegration - promoting effect;

[0118] Third, for the disintegration rate of the tablets in experimental protocol G, especially after 6 - month accelerated testing, compared with other groups, the reduction amplitude of the disintegration rate is more obvious, indicating that chitin and polyethylene glycol components are more conducive to maintaining the disintegration ability of the tablets in harsh environments; further combining experimental protocol B with experimental protocol A shows that the improvement effect of chitin and polyethylene glycol components on the disintegration rate is relatively slight.

[0119] Experimental Example 5

[0120] This experimental example tests the disintegration time of each protocol under the droplet method and controls the water droplet speed at 2 ml / min.

[0121] Specifically, after accelerating the tests of experimental protocols A - F according to the method of Experimental Example 2, the disintegration time is tested according to the method of Experimental Example 1. Each group of tests includes at least 1000 tablets, and the test data is as Figure 3 - Figure 4 shown, and this data is the average value of sampling and testing 10 tablets.

[0122] From Figure 3 , Figure 4 the experimental results, those skilled in the art can understand that: when there is sufficient moisture, the disintegration efficiency gap among each group is not large. The disintegration efficiency of experimental protocols D - G is slightly higher, but the disintegration efficiency of experimental protocol G is significantly lower after accelerated testing.

[0123] Example 1

[0124] Prepare salmon calcitonin liposomes: Mix phosphatidylcholine, sodium cholate, and cholesterol in a weight ratio of 4:0.5:1 to form complex B. Mix chloroform and methanol in a ratio of 0.5:1 to form solution A. Evaporate the organic solvents to obtain flexible liposomes; dissolve salmon calcitonin in phosphate - buffered solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Add liposomes according to the mass ratio of liposomes to salmon calcitonin solution of 8:1, hydrate for 1 hour, and then ultrasonically oscillate for 20 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension;

[0125] Chitin with a weight portion of 4 and polyethylene glycol 4000 with a weight portion of 4 were added to the salmon calcitonin liposome. After mixing, spray drying was carried out to obtain 20 parts of powder C. Powder C was mixed evenly with 0.5 part of D-mannitol, 0.4 part of lactose, 0.1 part of glycine, 50 parts of microcrystalline cellulose, 5 parts of low-substituted hydroxypropyl cellulose sodium, and 0.5 part of magnesium stearate, and then tabletted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0126] Example 2

[0127] Preparation of salmon calcitonin liposome: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a ratio of 5:0.2:1 by weight to form complex B. Chloroform and methanol were mixed in a ratio of 1:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension.

[0128] Chitin with a weight portion of 8 and polyethylene glycol 4000 with a weight portion of 8 were added to the salmon calcitonin liposome. After mixing, spray drying was carried out to obtain 21 parts of powder C. Powder C was mixed evenly with 1.2 parts of D-mannitol, 0.6 part of lactose, 0.2 part of glycine, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and then tabletted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0129] Example 3

[0130] Preparation of salmon calcitonin liposome: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a ratio of 6:0.1:1 by weight to form complex B. Chloroform and methanol were mixed in a ratio of 2:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 12:1, hydrated for 2 hours, and then ultrasonically oscillated for 40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension.

[0131] Chitin in an amount of 12 parts by weight and polyethylene glycol 4000 in an amount of 6 parts by weight were added to the salmon calcitonin liposome. After mixing, spray drying was carried out to obtain 30 parts of powder C. The powder C was mixed evenly with 1.4 parts of D-mannitol, 0.4 parts of lactose, 0.2 parts of glycine, 80 parts of microcrystalline cellulose, 15 parts of low-substituted hydroxypropyl cellulose sodium, and 2 parts of magnesium stearate, and then tabletted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0132] Example 4

[0133] Preparation of salmon calcitonin liposome: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a ratio of 4:0.5:1 by weight to form complex B. Chloroform and methanol were mixed in a ratio of 0.5:1 to form solution A. The organic solvent was evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Liposomes were added in a ratio of 8:1 by mass of liposome to salmon calcitonin solution, hydrated for 1 hour, and then ultrasonically oscillated for 20 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension.

[0134] 0.2 parts by weight of D-mannitol was dissolved in an appropriate amount of water to prepare a 10% mannitol solution; 0.4 parts of lactose, 0.1 parts of glycine, and the remaining 0.3 parts of D-mannitol were placed in a fluidized bed; the mannitol solution was used as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, drying was carried out at 55 °C for 30 min to obtain complex A particles; complex A with a particle size of 180 - 250 μm was screened; among them, in the step of spraying with the mannitol solution as the granulating agent, the pump flow rate was 30 L / h, the inlet air temperature of the fluidized bed was 45 °C, the inlet air volume was 15 m 3 / h, and the atomization pressure was 0.5 Bar.

[0135] Chitin in an amount of 4 parts by weight and polyethylene glycol 4000 in an amount of 4 parts by weight were added to the salmon calcitonin liposome. After mixing, spray drying was carried out to obtain 20 parts of powder C. The powder C was mixed evenly with 1 part of complex A, 50 parts of microcrystalline cellulose, 5 parts of low-substituted hydroxypropyl cellulose sodium, and 0.5 parts of magnesium stearate, and then tabletted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0136] Example 5

[0137] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol were mixed in a ratio of 1:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes were added at a mass ratio of liposomes to salmon calcitonin solution of 10∶1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were in the form of a suspension;

[0138] Take 0.72 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to prepare a 12% mannitol solution; take 0.6 parts of lactose, 0.2 parts of glycine, and the remaining 0.48 parts of D-mannitol, and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 55 °C for 40 min to obtain complex A particles; screen complex A with a particle size of 180 - 250 μm; among them, in the step of spraying with the mannitol solution as a granulating agent, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50 °C, the inlet air volume is 16 m 3 / h, and the atomization pressure is 0.8 Bar;

[0139] Add 8 parts by weight of chitin and 8 parts by weight of polyethylene glycol 4000 to the salmon calcitonin liposomes, mix them, and then spray-dry to obtain 21 parts of powder C. Mix powder C evenly with 2 parts of complex A, 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and press tablets to obtain calcitonin tablets, and the tablet weight is controlled at 250 mg.

[0140] Example 6

[0141] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 6:0.1:1 to form complex B. Chloroform and methanol were mixed in a ratio of 2:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 at a weight ratio of 1∶10 to form a salmon calcitonin solution. Liposomes were added at a mass ratio of liposomes to salmon calcitonin solution of 12:1, hydrated for 2 hours, and then ultrasonically oscillated for 40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were in the form of a suspension;

[0142] Take 0.7 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to prepare a 15% mannitol solution; take 0.4 parts of lactose, 0.2 parts of glycine, and the remaining 0.7 parts of D-mannitol, and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 60 °C for 60 min to obtain complex A particles; screen complex A with a particle size of 180 - 250 μm; among them, in the step of spraying with the mannitol solution as a granulating agent, the pump flow rate is 10 L / h, the inlet air temperature of the fluidized bed is 60 °C, the inlet air volume is 20 m 3 / h, and the atomization pressure is 1.0 Bar;

[0143] Add 12 parts by weight of chitin and 6 parts by weight of polyethylene glycol 4000 to the salmon calcitonin liposome, mix and then perform spray drying to obtain 30 parts of powder C. Mix the powder C evenly with 2 parts of complex A, 80 parts of microcrystalline cellulose, 15 parts of low-substituted hydroxypropyl cellulose sodium, and 2 parts of magnesium stearate, and press tablets to obtain calcitonin tablets, and the tablet weight is controlled at 250 mg.

[0144] Example 7

[0145] Prepare salmon calcitonin liposome: Mix phosphatidylcholine, sodium cholate, and cholesterol in a ratio of 4:0.5:1 by weight to form complex B. Mix chloroform and methanol in a ratio of 0.5:1 to form solution A, and evaporate to remove the organic solvent to obtain flexible liposomes; dissolve salmon calcitonin in a phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution, add liposomes in a ratio of 8:1 by mass of liposomes to the salmon calcitonin solution, hydrate for 1 hour, and then ultrasonically oscillate for 20 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension;

[0146] Take 0.2 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to prepare a 10% mannitol solution; take 0.4 parts of lactose, 0.1 parts of glycine, and the remaining 0.3 parts of D-mannitol, and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 55 °C for 30 min to obtain complex A particles; screen complex A with a particle size of 180 - 250 μm; among them, in the step of spraying with the mannitol solution as a granulating agent, the pump flow rate is 30 L / h, the inlet air temperature of the fluidized bed is 45 °C, the inlet air volume is 15 m 3 / h, and the atomization pressure is 0.5 Bar;

[0147] Chitosan with a weight portion of 4 and polyethylene glycol 4000 with a weight portion of 4 are added to the salmon calcitonin liposome. After mixing, spray drying is carried out to obtain 20 parts of powder C. The powder C is mixed evenly with 1 part of complex A, 50 parts of pregelatinized starch, 5 parts of sodium carboxymethyl starch, and 0.5 part of talc, and then tableted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0148] Example 8

[0149] Prepare salmon calcitonin liposome: Phosphatidylcholine, sodium cholate, and cholesterol are mixed in a ratio of 5:0.2:1 by weight to form complex B. Chloroform and methanol are mixed in a ratio of 1:1 to form solution A. The organic solvents are evaporated to obtain flexible liposomes. Salmon calcitonin is dissolved in phosphate buffer solution with a pH of 7 in a ratio of 1:10 by weight to form a salmon calcitonin solution. Liposomes are added in a ratio of 10:1 by mass of liposome to salmon calcitonin solution, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain the salmon calcitonin liposome, and the salmon calcitonin liposome is a suspension.

[0150] 0.72 parts by weight of D-mannitol is dissolved in an appropriate amount of water to prepare a 12% mannitol solution; 0.6 parts of lactose, 0.2 parts of glycine, and the remaining 0.48 parts of D-mannitol are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, drying is carried out at 55 °C for 40 min to obtain complex A particles; complex A with a particle size of 180 - 250 μm is screened; among them, in the step of spraying with the mannitol solution as the granulating agent, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50 °C, the inlet air volume is 16 m 3 / h, and the atomization pressure is 0.8 Bar.

[0151] Chitosan with a weight portion of 8 and polyethylene glycol 4000 with a weight portion of 8 are added to the salmon calcitonin liposome. After mixing, spray drying is carried out to obtain 21 parts of powder C. The powder C is mixed evenly with 2 parts of complex A, 65 parts of dextrin, 10 parts of cross-linked carboxymethyl cellulose sodium, and 1 part of colloidal silica, and then tableted to obtain the calcitonin tablets, with the tablet weight controlled at 250 mg.

[0152] Example 9

[0153] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 6:0.1:1 to form complex B. Chloroform and methanol were mixed in a ratio of 2:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 12:1, and hydrated for 2 hours, then ultrasonically oscillated for 40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were in the form of a suspension;

[0154] 0.7 parts by weight of D-mannitol was dissolved in an appropriate amount of water to prepare a 15% mannitol solution; 0.4 parts of lactose, 0.2 parts of glycine, and the remaining 0.7 parts of D-mannitol were placed in a fluidized bed; the mannitol solution was used as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, drying was carried out at 60 °C for 60 min to obtain complex A particles; complex A particles with a particle size of 180 - 250 μm were screened; among them, in the step of spraying with the mannitol solution as the granulating agent, the pump flow rate was 10 L / h, the inlet air temperature of the fluidized bed was 60 °C, the inlet air volume was 20 m 3 / h, and the atomization pressure was 1.0 Bar;

[0155] Chitin with a weight part of 12 and polyethylene glycol 4000 with a weight part of 6 were added to the salmon calcitonin liposomes, and after mixing, spray drying was carried out to obtain 30 parts of powder C. Powder C was mixed evenly with 2 parts of complex A, 80 parts of starch, 15 parts of cross-linked povidone, and 2 parts of magnesium stearate, and tabletted to obtain calcitonin tablets, and the tablet weight was controlled at 250 mg.

[0156] Comparative Example 1

[0157] This comparative example was basically the same as Example 2, except that:

[0158] Polyethylene glycol 4000 was replaced with oleic acid.

[0159] Comparative Example 2

[0160] This comparative example was basically the same as Example 5, except that:

[0161] Polyethylene glycol 4000 was replaced with oleic acid.

[0162] Comparative Example 3

[0163] This comparative example was basically the same as Example 5, except that:

[0164] Glycine was replaced with alanine.

[0165] Comparative Example 4

[0166] This comparative example is basically the same as Example 5, except that:

[0167] Glycine is replaced with tryptophan.

[0168] Comparative Example 5

[0169] This comparative example is basically the same as Example 5, except that:

[0170] Polyethylene glycol 4000 is not added.

[0171] Comparative Example 6

[0172] This comparative example is basically the same as Example 5, except that:

[0173] The steps for preparing Complex A are as follows:

[0174] Take 0.72 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to obtain a mannitol solution; take 0.6 parts of lactose, 0.2 parts of glycine, 0.2 parts of glucose, and the remaining 0.48 parts of D-mannitol, and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 55 °C for 40 min to obtain Complex A particles; screen Complex A with a particle size of 180 - 250 μm.

[0175] Comparative Example 7

[0176] This comparative example is basically the same as Example 5, except that:

[0177] The steps for preparing Complex A are as follows:

[0178] Take 0.72 parts by weight of D-mannitol and dissolve it in an appropriate amount of water to obtain a mannitol solution; take 0.6 parts of lactose, 0.2 parts of glycine, 0.2 parts of sucrose, and the remaining 0.48 parts of D-mannitol, and place them in a fluidized bed; use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; after spraying, dry at 55 °C for 40 min to obtain Complex A particles; screen Complex A with a particle size of 180 - 250 μm.

[0179] Comparative Example 8

[0180] This comparative example is basically the same as Example 5, except that:

[0181] The steps for preparing Complex A are as follows:

[0182] Take 1.2 parts by weight of D-mannitol, 0.6 parts of lactose, and 0.2 parts of glycine, dissolve them in an appropriate amount of water to obtain a solution, place it in a fluidized bed for spray drying, dry at 55 °C for 40 min to obtain Complex A particles; screen Complex A with a particle size of 180 - 250 μm.

[0183] Comparative Example 9

[0184] Preparation of salmon calcitonin liposomes: Phosphatidylcholine, sodium cholate, and cholesterol were mixed in a weight ratio of 5:0.2:1 to form complex B. Chloroform and methanol were mixed in a ratio of 1:1 to form solution A. The organic solvents were evaporated to obtain flexible liposomes. Salmon calcitonin was dissolved in phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution. Liposomes were added in a mass ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically oscillated for 30 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes were a suspension;

[0185] The salmon calcitonin liposomes were spray-dried to obtain 8 parts of powder C. Powder C was mixed evenly with 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate, and then tabletted to obtain calcitonin tablets, and the tablet weight was controlled at 250 mg.

[0186] Blank control

[0187] 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium, and 1 part of magnesium stearate were mixed evenly and tabletted to obtain calcitonin tablets, and the tablet weight was controlled at 250 mg.

[0188] Example 10

[0189] The pharmacodynamic effects of Examples 1-9 and Comparative Examples 1-9 were measured according to the method of Experimental Example 3.

[0190] The specific test method was as follows:

[0191] Take 0.5 ml of pure water to soak each sample for 1 min, and administer the soaked sample to experimental rats at a dose of 150 IU / kg body weight, and detect the pharmacodynamic effect. The experimental results are as Figure 5 - Figure 6 shown.

[0192] According to Figure 5 - Figure 6 the experimental results, it can be seen that:

[0193] First, comparing Examples 4-6 with Examples 1-3, their components are basically the same. The difference is that the step of preparing complex A is added in the process, so that the calcitonin tablets obtained in Examples 4-6 can lower the blood calcium concentration more in the first 1 h, and the state of hypocalcemia is maintained for a longer time (the blood calcium concentration ratio remains about 80% at 4 h), indicating that the step of preparing complex A in this application has a positive effect on the protection and absorption of calcitonin in the gastric environment. The applicant speculates that due to granulation, the particle size and pore size distribution of complex A are more uniform, increasing the disintegration efficiency and also having an adsorption effect on gastric acid;

[0194] Second, comparing Examples 4-6 with Examples 7-9, the difference is that they use different fillers, disintegrants or lubricants. It can be found that when comparing the two groups of examples, the technical effects of Examples 4-6 are slightly better.

[0195] Third, comparing Examples 2 and 5 with Comparative Examples 1-2 and Comparative Example 5, when the polyethylene glycol 4000 in the present application is replaced with the commonly used oleic acid component in the art or polyethylene glycol 4000 is not added, the maintenance time of the low blood calcium concentration is reduced. After 1 h, the blood calcium shows a gradually recovering trend. This shows that polyethylene glycol 4000 in the present application can play a technical effect of maintaining the blood calcium concentration in combination with other components.

[0196] Fourth, comparing Example 5 with Comparative Examples 3-4, when glycine in the complex A in the present application is replaced with other non-polar amino acids such as alanine and tryptophan, although there is a certain blood calcium lowering effect, there are certain differences compared with glycine, and the differences are significant.

[0197] Fifth, comparing Example 5 with Comparative Examples 6-7, adding glucose and sucrose to the complex A, especially adding sucrose, will cause a significant decrease in the blood calcium lowering effect and duration, indicating that the specific structure of the complex A has a positive effect on the protection and absorption of calcitonin in the gastric environment. Adding other components may damage this structure. Further, in Comparative Example 8, changing the preparation method of the complex A and directly mixing the components for spray granulation in a fluidized bed will also lead to a decrease in technical effects due to changing the structure of the complex A.

[0198] In summary, the calcitonin tablets provided by the present application can improve the disintegration speed of the drug, especially the disintegration speed in a less aqueous environment. On the one hand, it can improve the patient's medication taste, and on the other hand, it can also help improve the bioavailability of the drug, ensure the stable product quality, and improve the utilization rate of the product, having good commercial prospects.

[0199] For those of ordinary skill in the art, the technical features in the above examples can be freely combined, and the formed technical solutions also belong to the disclosed examples of the present application.

[0200] Furthermore, without departing from the principle of the present application, several improvements and modifications can be made to the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A calcitonin tablet, characterized in that: Composed of the following components by weight: 20 - 30 parts of the drug main body, 50 - 80 parts of the filler, 5 - 15 parts of the disintegrant, 0.5 - 2 parts of the lubricant, The drug main body includes 5 - 12 parts of salmon calcitonin liposome, 8 - 18 parts of the protective agent, and 1 - 2 parts of complex A, wherein the complex A includes lactose, D - mannitol, and glycine; The protective agent includes chitin and polyethylene glycol 4000, and the weight ratio of the two is 1 - 2∶1; Among them, the preparation method of the complex A includes: Take D - mannitol with a labeled amount of 40% - 60% and dissolve it in an appropriate amount of water to obtain a mannitol solution, Take lactose, glycine, and the remaining D - mannitol, and place them in a fluidized bed, Use the mannitol solution as a granulating agent for spraying to granulate the materials in the fluidized bed; After spraying, dry at 55 - 60 °C for 30 - 60 min to obtain complex A particles, Screen complex A with a particle size of 180 - 250 μm.

2. The calcitonin tablet according to claim 1, characterized in that: The weight ratio of lactose, D - mannitol, and glycine is 2 - 4∶5 - 8∶1.

3. The calcitonin tablet according to claim 1, characterized in that: The filler is one or a combination of several of starch, dextrin, microcrystalline cellulose, lactose, pre - gelatinized starch; the disintegrant is one or a combination of several of crospovidone, sodium carboxymethyl starch, sodium cross - carboxymethyl cellulose, low - substituted hydroxypropyl cellulose sodium; the lubricant is one or a combination of several of magnesium stearate, colloidal silicon dioxide, talc powder.

4. The calcitonin tablet according to any one of claims 1 to 3, characterized in that: The preparation method of the salmon calcitonin liposome includes the steps: Mix phosphatidylcholine, sodium cholate, and cholesterol in a weight ratio of 4 - 6∶0.1 - 0.5∶1 to form complex B, mix chloroform and methanol in a ratio of 0.5 - 2∶1 to form solution A, and evaporate to remove the organic solvent to obtain flexible liposomes; Dissolve salmon calcitonin in a phosphate buffer solution with a pH of 6 - 8 to form a salmon calcitonin solution, add liposomes in a mass ratio of liposome to salmon calcitonin of 8 - 12∶1, hydrate for 1 - 2 hours, and then ultrasonically oscillate for 20 - 40 min to obtain salmon calcitonin liposomes, and the salmon calcitonin liposomes are a suspension.

5. The calcitonin tablet according to claim 4, wherein: During the granulation process, the inlet air temperature of the fluidized bed is 45 - 60 °C, the inlet air volume is 15 - 20 m 3 / h, and the atomization pressure is 0.5 - 1.0 Bar.

6. The calcitonin tablet according to claim 5, wherein: After drying, the water content of the complex A particles is not higher than 8%.

7. The calcitonin tablet according to claim 6, characterized in that: After drying, the water content of the complex A particles is 4 - 6%.

8. The calcitonin tablet according to claim 6 or 7, characterized in that: The complex A does not contain glucose and sucrose.

9. A preparation method of a calcitonin tablet according to any one of claims 1 - 8, characterized in that: It includes the steps: Prepare salmon calcitonin liposomes from the labeled amount of salmon calcitonin, and the salmon calcitonin liposomes are a suspension; Prepare complex A in a fluidized bed; Add the labeled amount of chitin and polyethylene glycol 4000 to the salmon calcitonin liposomes, mix and then spray - dry to obtain powder C, mix the powder C with complex A, and press into tablets to obtain calcitonin tablets.

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