Calcitonin tablet and preparation method thereof

Abstract

The invention relates to the technical field of biological medicines, in particular to a calcitonin tablet and a preparation method thereof. Wherein the calcitonin tablet comprises the following components in parts by weight: 20-30 parts of a drug main body, 50-80 parts of a filler, 5-15 parts of a disintegrating agent 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 a compound A, and the compound A comprises lactose, D-mannitol and glycine. According to the technical scheme, the compound A is added into the components, so that the disintegration speed of the medicine can be increased, especially the disintegration speed in a low-water environment, on one hand, the medicine taking taste of a patient can be improved, and on the other hand, the bioavailability of the medicine can be improved.

Description

Technical Field

[0001] The present application relates to the technical field of biological medicines, and in particular, to a calcitonin tablet and a preparation method thereof. Background Art

[0002] Osteoporosis is a disease characterized by decreased bone mass, reduced bone strength, increased bone brittleness, and increased susceptibility to fractures. As the world's population continues to age, osteoporosis will become a large-scale global health problem. Currently, typical therapeutic drugs are mainly bone resorption inhibitors, of which calcitonin products account for more than half of the market.

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

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

[0005] In view of this, this application is filed. 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 technical problem described in the background technology.

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

[0008] 20-30 copies of the main drug,

[0009] Filler 50-80 parts,

[0010] Disintegrant 5-15 parts,

[0011] Lubricant 0.5-2 parts,

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

[0013] By adopting the above technical solution, by adding complex A to the components, the disintegration rate of the drug can be increased, especially the disintegration rate in a water-poor environment. On the one hand, it can improve the patient's taste of taking the medicine, and on the other hand, it can also help improve the bioavailability of the drug.

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

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

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

[0017] 24 parts of the drug body,

[0018] Filler 65 parts,

[0019] Disintegrant 10 parts,

[0020] 1 part lubricant,

[0021] The drug body comprises 8 parts of salmon calcitonin liposomes, 14 parts of protective agents, and 2 parts of complex A, wherein the complex A comprises 0.6 parts of lactose, 1.2 parts of D-mannitol, and 0.2 parts of glycine.

[0022] Preferably, the method for preparing salmon calcitonin liposomes comprises the steps of:

[0023] Phosphatidylcholine and sodium cholate are mixed in a weight ratio of 4-6:0.1-0.5:1 with cholesterol to form a complex B, chloroform and methanol are mixed in a weight ratio of 0.5-2:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome;

[0024] The salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 6-8 to form a salmon calcitonin solution, liposomes are added at a mass ratio of liposomes to salmon calcitonin of 8-12:1, hydrated for 1-2 hours, and then ultrasonically vibrated for 20-40 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension.

[0025] Preferably, the evaporation is rotary evaporation.

[0026] Preferably, the salmon calcitonin is dissolved in a phosphate buffer solution at a pH of 7.0.

[0027] Preferably, the liposomes are added at a mass ratio of 10:1 between the liposomes and the salmon calcitonin, and hydrated for 90 minutes, followed by ultrasonic oscillation for 30 minutes.

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

[0029] Take 40%-60% of the labeled amount of D-mannitol and dissolve it in an appropriate amount of water to prepare a mannitol solution.

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

[0031] The mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed;

[0032] After spraying, the particles are dried at 55-60°C for 30-60 minutes to obtain the composite A particles.

[0033] The particle size of the composite A was 180-250 μm.

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

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

[0036] Preferably, during the granulation process, the material temperature is not higher than 50°C, preferably 30-40°C.

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

[0038] Preferably, after drying, the water content of the composite A particles is not higher than 8%, preferably 4-6%.

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

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

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

[0042] Preferably, the lubricant is one or a combination of magnesium stearate, micro-powdered silica gel and talc.

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

[0044] The second aspect of the present application provides a method for preparing the calcitonin tablet as described in the first aspect, comprising the steps of:

[0045] Prepare salmon calcitonin liposomes by adding a labeled amount of salmon calcitonin, wherein the salmon calcitonin liposomes are a suspension;

[0046] preparing composite A in a fluidized bed;

[0047] The indicated amount of chitosan and polyethylene glycol 4000 were added to the salmon calcitonin liposomes, mixed and spray-dried to obtain powder C, and the powder C was mixed with the complex A and tabletted to obtain calcitonin tablets.

[0048] Preferably, the step of preparing salmon calcitonin liposomes from a labeled amount of salmon calcitonin comprises the steps of:

[0049] Phosphatidylcholine and sodium cholate are mixed in a weight ratio of 4-6:0.1-0.5:1 with cholesterol to form a complex B, chloroform and methanol are mixed in a weight ratio of 0.5-2:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome;

[0050] The salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 6-8 to form a salmon calcitonin solution, liposomes are added at a mass ratio of liposomes to salmon calcitonin of 8-12:1, hydrated for 1-2 hours, and then ultrasonically vibrated for 20-40 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension.

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

[0052] Take 40%-60% of the labeled amount of D-mannitol and dissolve it 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] The mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed;

[0055] After spraying, the particles are dried at 55-60°C for 30-60 minutes to obtain the composite A particles.

[0056] The particle size of the composite A was 180-250 μm.

[0057] Preferably, the evaporation is rotary evaporation.

[0058] Preferably, the salmon calcitonin is dissolved in a phosphate buffer solution at a pH of 7.0.

[0059] Preferably, the liposomes are added at a mass ratio of 10:1 between the liposomes and the salmon calcitonin, and hydrated for 90 minutes, followed by ultrasonic oscillation for 30 minutes.

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

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

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

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

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

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

[0066] 1. The calcitonin tablets provided in the present application can increase the disintegration rate of the drug by adding complex A to the components, especially the disintegration rate in a water-poor environment. On the one hand, it can improve the patient's taste of the drug, and on the other hand, it can also help improve the bioavailability of the drug.

[0067] 2. The calcitonin tablets provided in the present application, by adding chitosan and polyethylene glycol 4000 as protective agents, can reduce the effect of gastric acid on the activity of calcitonin after administration and improve the bioavailability of the drug.

[0068] 3. The preparation method of calcitonin tablets provided in the present application can obtain tablets with more stable quality and faster disintegration rate by preparing salmon calcitonin liposomes and complex A, and mixing the two and then tableting, thereby ensuring product quality while increasing the bioavailability of the drug and having good commercial prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 The disintegration rate under low water conditions on day 0 of the accelerated test of experimental scheme AG in Experimental Example 4 of this application;

[0070] Figure 2 The disintegration rate of experimental scheme AG in experimental example 4 of this application under low water conditions at the 6th month of the accelerated test;

[0071] Figure 3 The disintegration rate of experimental scheme AG in experimental example 4 of the present application under flood conditions on day 0 of the accelerated test;

[0072] Figure 4The disintegration rate of Experimental Scheme AG in Experimental Example 4 of this application in the 6th month of the accelerated test under flood conditions;

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

[0074] Figure 6 It is the blood calcium concentration ratio of comparative examples 1-9 of the present application. DETAILED DESCRIPTION

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

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

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

[0078] In the prior art, salmon calcitonin is widely used in the treatment of osteoporosis, but the common dosage forms of salmon calcitonin include injections and nasal sprays, and the patient compliance and bioavailability are poor. Although oral preparations of calcitonin have been proposed, there is still room for improvement in its bioavailability in the body. In particular, the applicant found that osteoporosis patients are often accompanied by dry mouth and other phenomena, and the existing calcitonin tablets do not disintegrate well in the oral cavity in the absence of water, which affects its absorption in the stomach.

[0079] In view of this, the inventive concept of the present application is to provide a calcitonin tablet, which includes components by weight: 20-30 parts of the drug body, 50-80 parts of the filler, 5-15 parts of the disintegrant, and 0.5-2 parts of the lubricant. The drug body includes 5-15 parts of salmon calcitonin liposomes, 8-18 parts of the protective agent, and 1-5 parts of the complex A, wherein the complex A includes lactose, D-mannitol, and glycine. By adopting the technical solution of the present application, by adding the complex A to the components, the disintegration rate of the drug can be increased, especially the disintegration rate in a water-poor environment, which can improve the patient's taste of the drug on the one hand, and help improve the bioavailability of the drug on the other hand.

[0080] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods. Those skilled in the art should also understand that the reaction time and drug feeding involved in this application cannot be absolutely accurate in the actual production process, but are all within the allowable error range. For example, if you expect to heat the sample for 30 minutes, the actual operation may be 1 second more or less than 1 second in 30 minutes; if you expect to weigh 30g of sample, you may actually weigh 30.001g or 29.998g.

[0081] Experimental Example 1: Liquid drop method disintegration test

[0082] The measuring device in this experimental example is mainly composed of an iron frame, a screen, a burette, and a liquid receiving device. The burette is fixed at a specific position of the iron frame and can be adjusted in height; the liquid receiving device is arranged at the bottom of the iron frame, and the projection of the burette on the bottom surface is located in the liquid receiving device, so that the liquid receiving device can collect the liquid dripped from the burette; the screen is located on the liquid receiving device, used to carry tablets, the screen is 40 mesh, and the tablet is located on the moving path of the liquid dripped from the burette, so that the liquid can contact and wet the tablet.

[0083] The determination method is as follows: fill the burette with 37°C water, control the water drop rate to 0.5ml / min or 2ml / min, and keep the vertical distance between the water droplet and the tablet at 2cm to prevent the tablet from being impacted by the high distance. Place the tablet on the screen so that the water in the burette can just drip onto the tablet, start timing, and record the time when the tablet dissolves and leaks from the screen as the disintegration time. Test the disintegration efficiency of the tablet at 1min, 2min, and 3min respectively, that is, divide it into three groups of 1min, 2min, and 3min. 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 samples and place them at 40℃±2℃, RH75%±5% for 6 months.

[0086] Experimental Example 3: Drug Efficacy Test

[0087] Experimental method: SD female rats weighing 200±20g were fasted overnight the day before and fasted on the day of administration, and fed 8h after administration. The rats were randomly divided into groups, 4 rats in each group, and calcitonin tablets of different components were administered orally at a dose of 150IU / kg body weight.

[0088] Detection method: Serum calcium concentration was determined using the OCPC o-cresolphthalein complexation kit: Blood was collected from the rat tail vein at 0, 1, 2, 4, and 8 hours after administration, with 0.3 ml of blood collected each time. The blood sample was centrifuged at 4000 rpm within 30 minutes to separate the serum. Each blood sample was measured 3 times and the average value was taken. The blood calcium concentration ratio was calculated, which was calculated with the serum calcium concentration at 0 hours as the denominator and the blood calcium concentration at other time points as the numerator.

[0089] Experimental Example 4

[0090] This experimental example tests the disintegration time of each experimental scheme under the droplet method, and controls the water droplet speed to 0.5 ml / min.

[0091] Experimental plan A

[0092] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0093] The salmon calcitonin liposomes were spray-dried 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 compressed into tablets to obtain calcitonin tablets, and the tablet weight was controlled at 500 mg.

[0094] Experimental plan B

[0095] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 min to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0096] 7 parts by weight of chitin and 7 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 22 parts of powder C, and the powder C is evenly mixed with 65 parts of microcrystalline cellulose, 10 parts of low-substituted hydroxypropyl cellulose sodium and 1 part of magnesium stearate, and compressed to obtain calcitonin tablets, and the tablet weight is controlled at 500 mg.

[0097] Experimental plan C

[0098] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0099] 7 parts by weight of chitin and 7 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 22 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled to be 500 mg.

[0100] Experimental plan D

[0101] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0102] 7 parts by weight of chitin and 7 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 22 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled to be 500 mg.

[0103] Experimental plan E

[0104] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0105] 7 parts by weight of chitin and 7 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 22 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled to be 500 mg.

[0106] Experimental Plan F

[0107] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 58° C. for 40 minutes to obtain complex A particles; and complex A with a particle size of 180-250 μm is screened; wherein, in the step of using the mannitol solution as a granulating agent for spraying, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50° C., and the inlet air volume is 16 m 3 / h, atomization pressure is 0.8Bar;

[0109] 7 parts by weight of chitin and 7 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 22 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, and the tablet weight is controlled at 500 mg.

[0110] Experimental plan G

[0111] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0112] 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 58° C. for 40 minutes to obtain complex A particles; and complex A with a particle size of 180-250 μm is screened; wherein, in the step of using the mannitol solution as a granulating agent for spraying, the pump flow rate is 20 L / h, the inlet air temperature of the fluidized bed is 50° C., and the inlet air volume is 16 m 3 / h, atomization pressure is 0.8Bar;

[0113] The salmon calcitonin liposomes were spray-dried to obtain powder C. 8 parts of powder C were taken by weight, mixed 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 compressed into tablets to obtain calcitonin tablets. The tablet weight was controlled at 500 mg.

[0114] After the accelerated test of Experimental Schemes A to G was carried out according to the method of Experimental Example 2, the disintegration time was tested according to the method of Experimental Example 1. Each group of tests included at least 1000 tablets. The test data are as follows: Figure 1-Figure 2 As shown, the data is the average value of 10 samples tested.

[0115] Depend on Figure 1 , Figure 2 The experimental results of those skilled in the art can be understood:

[0116] First, comparing Experimental Scheme C with Experimental Schemes AB, the disintegration rate of Experimental Scheme C was significantly improved, and the applicant speculated that this was due to the good water solubility of D-mannitol;

[0117] Second, comparing experimental schemes CE, the difference is that experimental schemes D and E add lactose and glycine components on the basis of C, but the disintegration rates of the three are not significantly different; further, comparing experimental schemes F and E, the components used in the two are basically the same, but in experimental scheme F, D-mannitol, lactose, and glycine are prepared into complex A by fluidized bed granulation, which makes it have a better disintegration-promoting effect;

[0118] Third, the disintegration rate of the tablets in Experimental Scheme G, especially after 6 months of accelerated testing, was more significantly reduced compared with other groups, indicating that the chitin and polyethylene glycol components are more conducive to maintaining the disintegration ability of the tablets under harsh environments; further combining Experimental Schemes B and A, it can be seen that the effect of chitin and polyethylene glycol components on improving the disintegration rate is relatively slight.

[0119] Experimental Example 5

[0120] This experimental example tests the disintegration time of each solution under the droplet method, and controls the droplet speed to 2 ml / min.

[0121] Specifically, after the accelerated test of Experimental Scheme A to Experimental Scheme F according to the method of Experimental Example 2, the disintegration time was tested according to the method of Experimental Example 1. Each group of tests included at least 1000 tablets. The test data are as follows: Figure 3-Figure 4 As shown, the data is the average value of 10 samples tested.

[0122] Depend on Figure 3 , Figure 4 From the experimental results, those skilled in the art can understand that: under the condition of sufficient water, the disintegration efficiency of each group is not much different, the disintegration efficiency of experimental scheme DG is slightly higher, but the disintegration efficiency of experimental scheme G is obviously lower after the accelerated test.

[0123] Example 1

[0124] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 4:0.5:1, and cholesterol is mixed at a weight ratio of 0.5:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 0.5:1 to form a solution A, and the organic solvent is removed by evaporation to obtain flexible liposomes; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and liposomes are added at a weight ratio of 8:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 20 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0125] 4 parts by weight of chitin and 4 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 20 parts of powder C, and the powder C is evenly mixed with 0.5 parts of D-mannitol, 0.4 parts of lactose, 0.1 parts of glycine, 50 parts of microcrystalline cellulose, 5 parts of low-substituted hydroxypropyl cellulose sodium, and 0.5 parts of magnesium stearate, and tableted to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0126] Example 2

[0127] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed with cholesterol in a weight ratio of 5:0.2:1 to form a complex B, chloroform and methanol are mixed in a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added in a weight ratio of liposomes to salmon calcitonin solution of 10:1, hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0128] 8 parts by weight of chitin and 8 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 21 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0129] Example 3

[0130] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed with cholesterol in a weight ratio of 6:0.1:1 to form a complex B, chloroform and methanol are mixed in a weight ratio of 2:1 to form a solution A, and the organic solvent is removed by evaporation to obtain flexible liposomes; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution, and liposomes are added in a weight ratio of liposomes to salmon calcitonin solution of 12:1, hydrated for 2 hours, and then ultrasonically vibrated for 40 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0131] 12 parts by weight of chitin and 6 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 30 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0132] Example 4

[0133] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 4:0.5:1, and cholesterol is mixed at a weight ratio of 0.5:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 0.5:1 to form a solution A, and the organic solvent is removed by evaporation to obtain flexible liposomes; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and liposomes are added at a weight ratio of 8:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 20 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0134] 0.2 parts by weight of D-mannitol is 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 are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 55° C. for 30 minutes to obtain complex A particles; and the complex A with a particle size of 180-250 μm is screened; wherein, 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., and the inlet air volume is 15 m 3 / h, atomization pressure is 0.5Bar;

[0135] 4 parts by weight of chitin and 4 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 20 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0136] Example 5

[0137] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0138] 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the particles are dried at 55° C. for 40 minutes to obtain complex A particles; and complex A with a particle size of 180-250 μm is screened; wherein, 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., and the inlet air volume is 16 m 3 / h, atomization pressure is 0.8Bar;

[0139] 8 parts by weight of chitin and 8 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 21 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled to be 250 mg.

[0140] Example 6

[0141] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 6:0.1:1, and cholesterol is mixed at a weight ratio of 2:1 to form a solution A, and the organic solvent is removed by evaporation to obtain flexible liposomes; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 12:1 to the salmon calcitonin solution, and the liposomes are hydrated for 2 hours, and then ultrasonically vibrated for 40 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0142] 0.7 parts by weight of D-mannitol is 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 are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 60° C. for 60 minutes to obtain composite A particles; and composite A with a particle size of 180-250 μm is screened; wherein, in the step of using the mannitol solution as a granulating agent for spraying, the pump flow rate is 10 L / h, the inlet air temperature of the fluidized bed is 60° C., and the inlet air volume is 20 m 3 / h, atomization pressure is 1.0Bar;

[0143] 12 parts by weight of chitin and 6 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 30 parts of powder C, and the powder C is evenly mixed 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 compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0144] Example 7

[0145] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 4:0.5:1, and cholesterol is mixed at a weight ratio of 0.5:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 0.5:1 to form a solution A, and the organic solvent is removed by evaporation to obtain flexible liposomes; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and liposomes are added at a weight ratio of 8:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 20 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0146] 0.2 parts by weight of D-mannitol is 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 are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 55° C. for 30 minutes to obtain complex A particles; and the complex A with a particle size of 180-250 μm is screened; wherein, 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., and the inlet air volume is 15 m 3 / h, atomization pressure is 0.5Bar;

[0147] 4 parts by weight of chitin and 4 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 20 parts of powder C, and the powder C is evenly mixed with 1 part of complex A, 50 parts of pregelatinized starch, 5 parts of sodium carboxymethyl starch, and 0.5 parts of talc, and compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0148] Example 8

[0149] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the particles are dried at 55° C. for 40 minutes to obtain complex A particles; and complex A with a particle size of 180-250 μm is screened; wherein, 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., and the inlet air volume is 16 m 3 / h, atomization pressure is 0.8Bar;

[0151] 8 parts by weight of chitin and 8 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 21 parts of powder C, and the powder C is evenly mixed with 2 parts of complex A, 65 parts of dextrin, 10 parts of cross-linked sodium carboxymethyl cellulose, and 1 part of micro-powder silica gel, and the calcitonin tablets are prepared by tableting, and the tablet weight is controlled at 250 mg.

[0152] Example 9

[0153] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate and cholesterol are mixed in a weight ratio of 6:0.1:1 to form a complex B, chloroform and methanol are mixed in a weight ratio of 2:1 to form a solution A, and the organic solvent is evaporated to remove to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 in a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added in a weight ratio of liposomes to salmon calcitonin solution of 12:1, hydrated for 2 hours, and then ultrasonically vibrated for 40 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

[0154] 0.7 parts by weight of D-mannitol is 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 are placed in a fluidized bed; the mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 60° C. for 60 minutes to obtain composite A particles; and composite A with a particle size of 180-250 μm is screened; wherein, in the step of using the mannitol solution as a granulating agent for spraying, the pump flow rate is 10 L / h, the inlet air temperature of the fluidized bed is 60° C., and the inlet air volume is 20 m 3 / h, atomization pressure is 1.0Bar;

[0155] 12 parts by weight of chitin and 6 parts by weight of polyethylene glycol 4000 are added to the salmon calcitonin liposomes, mixed and spray-dried to obtain 30 parts of powder C, and the powder C is evenly mixed with 2 parts of complex A, 80 parts of starch, 15 parts of cross-linked polyvinylpyrrolidone, and 2 parts of magnesium stearate, and compressed to obtain calcitonin tablets, wherein the tablet weight is controlled at 250 mg.

[0156] Comparative Example 1

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

[0158] Replace polyethylene glycol 4000 with oleic acid.

[0159] Comparative Example 2

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

[0161] Replace polyethylene glycol 4000 with oleic acid.

[0162] Comparative Example 3

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

[0164] Replace glycine with alanine.

[0165] Comparative Example 4

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

[0167] Replace glycine with tryptophan.

[0168] Comparative Example 5

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

[0170] No polyethylene glycol 4000 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:

[0174] 0.72 parts by weight of D-mannitol is dissolved in an appropriate amount of water to prepare a mannitol solution; 0.6 parts of lactose, 0.2 parts of glycine, 0.2 parts of glucose, 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 55° C. for 40 minutes to obtain complex A particles; and the complex A with a particle size of 180-250 μm is screened.

[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:

[0178] 0.72 parts by weight of D-mannitol is dissolved in an appropriate amount of water to obtain a mannitol solution; 0.6 parts of lactose, 0.2 parts of glycine, 0.2 parts of sucrose, 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 achieve granulation of the material in the fluidized bed; after the spraying is completed, the material is dried at 55° C. for 40 minutes to obtain complex A particles; and the complex A with a particle size of 180-250 μm is screened.

[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:

[0182] 1.2 parts by weight of D-mannitol, 0.6 parts by weight of lactose and 0.2 parts by weight of glycine were dissolved in an appropriate amount of water to obtain a solution, which was placed in a fluidized bed for spray drying and dried at 55° C. for 40 minutes to obtain complex A particles; and complex A with a particle size of 180-250 μm was screened.

[0183] Comparative Example 9

[0184] Preparation of salmon calcitonin liposomes: phosphatidylcholine and sodium cholate are mixed at a weight ratio of 5:0.2:1, and cholesterol is mixed at a weight ratio of 1:1 to form a complex B, chloroform and methanol are mixed at a weight ratio of 1:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome; salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 7 at a weight ratio of 1:10 to form a salmon calcitonin solution, and the liposomes are added at a weight ratio of 10:1 to the salmon calcitonin solution, and the liposomes are hydrated for 1 hour, and then ultrasonically vibrated for 30 minutes to obtain salmon calcitonin liposomes, wherein the salmon calcitonin liposomes are a suspension;

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

[0188] Example 10

[0189] The efficacy of Examples 1-9 and Comparative Examples 1-9 was determined according to the method of Experimental Example 3.

[0190] The specific test method is:

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

[0192] according to Figure 5-Figure 6 The experimental results show that:

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

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

[0195] Third, by 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 oleic acid component commonly used in the art, or when the polyethylene glycol 4000 is not added, the maintenance time of the low blood calcium concentration is reduced, and after 1 hour, the blood calcium shows a trend of gradual recovery, which indicates that the polyethylene glycol 4000 in the present application, in combination with other components, can play a technical effect of maintaining the blood calcium concentration;

[0196] Fourth, by comparing Example 5 with Comparative Examples 3-4, after replacing glycine in the complex A of the present application with other non-polar amino acids such as alanine and tryptophan, although there is a certain effect of lowering blood calcium, there is a certain difference compared with glycine, and the difference is significant;

[0197] Fifth, by comparing Example 5 with Comparative Examples 6-7, the addition of glucose and sucrose to Complex A, especially the addition of sucrose, will lead to a significant decrease in the effect and duration of hypocalcemia, indicating that the specific structure of Complex A has a positive effect on the protection and absorption of calcitonin in the gastric environment, and the additional addition of other components may destroy the structure; further, in Comparative Example 8, the preparation method of Complex A is changed, and the components are directly mixed in a fluidized bed for spray granulation, which will also reduce the technical effect due to the change in the structure of Complex A.

[0198] In summary, the calcitonin tablets provided in the present application can increase the disintegration rate of the drug, especially the disintegration rate in a water-poor environment. On the one hand, it can improve the patient's taste of taking the medicine, and on the other hand, it can also help improve the bioavailability of the drug, while ensuring the stability of product quality, and improving the utilization rate of the product, which has a good commercial prospect.

[0199] For ordinary technicians in this field, the technical features in the above embodiments can be freely combined, and the formed technical solutions also belong to the embodiments disclosed in this application.

[0200] Furthermore, without departing from the principles of the present application, several improvements and modifications may 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: By weight, including components: 20-30 copies of the main drug, Filler 50-80 parts, Disintegrant 5-15 parts, Lubricant 0.5-2 parts, The drug main body comprises 5-12 parts of salmon calcitonin liposomes, 8-18 parts of protective agents, and 1-2 parts of complex A, wherein the complex A comprises lactose, D-mannitol, and glycine.

2. The calcitonin tablet according to claim 1, characterized in that: The protective agent comprises chitosan and polyethylene glycol 4000, and the weight ratio of the two is 1-2:

1.

3. 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.

4. The calcitonin tablet according to claim 1, characterized in that: The filler is one or a combination of starch, dextrin, microcrystalline cellulose, lactose, and pregelatinized starch; the disintegrant is one or a combination of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted sodium hydroxypropyl cellulose; the lubricant is one or a combination of magnesium stearate, micro-powdered silica gel, and talc.

5. The calcitonin tablet according to any one of claims 1 to 4, characterized in that: The preparation method of salmon calcitonin liposomes comprises the steps of: Phosphatidylcholine and sodium cholate are mixed with cholesterol in a weight ratio of 4-6:0.1-0.5:1 to form a complex B, chloroform and methanol are mixed in a weight ratio of 0.5-2:1 to form a solution A, and the organic solvent is removed by evaporation to obtain a flexible liposome; The salmon calcitonin is dissolved in a phosphate buffer solution with a pH of 6-8 to form a salmon calcitonin solution, and the liposomes are added in a ratio of 8-12:1 to the salmon calcitonin mass ratio, hydrated for 1-2 hours, and then ultrasonically vibrated for 20- After 40 minutes, salmon calcitonin liposomes were obtained, and the salmon calcitonin liposomes were in the form of a suspension.

6. The calcitonin tablet according to claim 5, characterized in that: The preparation method of compound A comprises: Take 40%-60% of the labeled amount of D-mannitol and dissolve it in an appropriate amount of water to prepare a mannitol solution. Take lactose, glycine, and the remaining D-mannitol and place them in a fluidized bed. The mannitol solution is used as a granulating agent for spraying to achieve granulation of the material in the fluidized bed; After spraying, the particles are dried at 55-60°C for 30-60 minutes to obtain the composite A particles. The particle size of the composite A was screened to be 180-250 μm.

7. The calcitonin tablet according to claim 6, characterized in that: During the granulation process, the inlet air temperature of the fluidized bed is 45-60°C, and the inlet air volume is 15-20m 3 / h, the atomization pressure is 0.5-1.0Bar.

8. The calcitonin tablet according to claim 6, characterized in that: After drying, the water content of the composite A particles is not higher than 8%, preferably 4-6%.

9. The calcitonin tablet according to any one of claims 6 to 8, characterized in that: The complex A does not contain glucose or sucrose.

10. A method for preparing the calcitonin tablet according to any one of claims 1 to 9, characterized in that: Includes steps: Prepare salmon calcitonin liposomes by adding a labeled amount of salmon calcitonin, wherein the salmon calcitonin liposomes are a suspension; preparing composite A in a fluidized bed; The indicated amount of chitosan and polyethylene glycol 4000 were added to the salmon calcitonin liposomes, mixed and spray-dried to obtain powder C, and the powder C was mixed with the complex A and tabletted to obtain calcitonin tablets.

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