A blood sugar lowering pharmaceutical preparation

Abstract

The present invention discloses a hypoglycemic pharmaceutical preparation, relating to the technical field of preparation of hypoglycemic pharmaceutical preparations. The preparation comprises active ingredients and medically acceptable excipients; the active ingredients include semaglutide and canagliflozin; the medically acceptable excipients include a buffer, an excipient, an isotonic agent, and / or a stabilizer; and the preparation is a lyophilized powder prepared using a staged lyophilization process. This preparation utilizes an advanced lyophilization process, which not only significantly improves its overall quality but also significantly reduces the adverse effects of temperature on the preparation's performance.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of hypoglycemic pharmaceutical preparations, and more particularly to hypoglycemic pharmaceutical preparations. Background Art

[0002] Type 2 diabetes mellitus (T2DM) is a common, chronic metabolic disease characterized by hyperglycemia, insulin resistance, and insufficient insulin secretion, resulting from a combination of genetic and environmental factors. Its pathophysiology is characterized by a decrease in insulin's ability to regulate glucose metabolism (insulin resistance), accompanied by insufficient (or relatively reduced) insulin secretion due to defective pancreatic beta-cell function.

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin secreted by intestinal L cells. It acts on GLP-1 receptors on pancreatic islet cells, enhancing insulin secretion and inhibiting glucagon secretion, thereby lowering blood sugar. Semaglutide is a novel long-acting GLP-1 receptor agonist based on the human GLP-1 molecule. Alanine is substituted with α-aminoisobutyric acid at position 8 to increase resistance to degradation by the DPP-4 enzyme, thereby extending semaglutide's plasma half-life. A C-18 fatty diacid side chain, separated by glutamic acid, is attached to lysine at position 26, increasing its affinity for albumin and preventing rapid renal clearance. Arginine is substituted for lysine at position 34 to increase side chain stability.

[0004] After binding to the GLP-1 receptor, semaglutide stimulates insulin secretion from pancreatic beta cells in a blood glucose-dependent manner, improving the abnormal insulin secretion pattern in patients with type 2 diabetes. This enhances first-phase insulin secretion, making insulin secretion more consistent with physiological needs and better controlling postprandial blood glucose fluctuations. It also inhibits glucagon secretion from pancreatic alpha cells, reducing hepatic glycogen breakdown and gluconeogenesis, thereby lowering fasting blood glucose levels. Long-term use of semaglutide can improve pancreatic beta cell function and survival. This may improve insulin secretion by alleviating intracellular damage mechanisms such as endoplasmic reticulum stress and oxidative stress, reducing beta cell apoptosis, and increasing beta cell number and function, thus providing long-term benefits in the treatment of type 2 diabetes.

[0005] Amylin, also known as islet amyloid polypeptide (IAPP), is a hormone secreted by pancreatic β-cells. It coexists with insulin in these cells, rising and falling in sync. It is co-secreted into the portal circulation at a constant molar ratio with insulin in response to nutrient intake. It plays a role in glucose homeostasis by blocking glucose release from the liver, delaying gastric emptying, and signaling satiety. Cagrilintide is an investigational, novel, long-acting, acylated amylin analog that acts as a non-selective agonist of the amylin receptor (AMYR) and calcitonin G-protein-coupled receptor (CTR). Studies have shown that stimulating the calcitonin receptor with peptides such as canagliflozin may help lower blood glucose levels in patients with T2D. In the brain, canagliflozin targets the islet amylin receptor, located in key areas of appetite regulation, including the nucleus tractus solitarius (NTS) and area postrema (AP). This action can reduce food consumption and contribute to weight loss. By activating these receptors, canagliflozin also slows gastric emptying and inhibits glucagon secretion, thereby prolonging feelings of fullness after eating and helping to maintain stable blood sugar levels. This can aid in weight management and improve overall metabolic health.

[0006] CagriSema is a compound preparation developed by Novo Nordisk Co., Ltd., containing semaglutide and canagliflozin as active ingredients. It is used for type 2 diabetes and weight management and is currently in Phase 3 clinical trials. CN 115135305A discloses a pharmaceutical preparation, which is an aqueous pharmaceutical preparation composed of semaglutide and canagliflozin and a dedicated drug delivery device designed for the preparation. The device is loaded with canagliflozin injection near the front end of the syringe and semaglutide injection at the distal end. Before clinical administration, the two injections are mixed in the device and administered subcutaneously. The preparation process of this pharmaceutical preparation is cumbersome, requiring the two injections to be prepared separately and loaded into a specific drug delivery device, which invisibly increases the production cost of the pharmaceutical preparation and the cost of medication for clinical patients. Moreover, many current hypoglycemic preparations composed of semaglutide and canagliflozin have poor stability due to limitations in the preparation process, are inconvenient to store and transport, and have uncontrollable impurity content, which greatly reduces the drug effect.

[0007] CN 118382451 A discloses a pharmaceutical formulation consisting of semaglutide and canagliflozin, containing hydroxypropyl-beta-cyclodextrin and polysorbate as excipients. Hydroxypropyl-beta-cyclodextrin serves as a stabilizer for the active ingredient (to reduce aggregate formation in the polypeptide molecules), while polysorbate further enhances the physical stability of the drug during storage and use. The hydroxypropyl-beta-cyclodextrin contained in the formulation is a commonly used excipient, but its production cost is relatively high, especially for injectable-grade hydroxypropyl-beta-cyclodextrin, which requires special modification. Furthermore, the patent does not specify the typical storage conditions for the formulation. Based on the patent content, it is speculated that additional cold chain management measures may be required during actual production or transportation of the formulation, which would inadvertently increase the production and storage costs.

[0008] Therefore, how to provide a preparation with good stability and low impurity content is a technical problem that those skilled in the art urgently need to solve. Summary of the Invention

[0009] In view of this, the present invention is proposed.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] In one aspect, an embodiment of the present invention provides a hypoglycemic pharmaceutical preparation comprising an active ingredient and medically acceptable excipients; the active ingredient comprises semaglutide and canagliflozin; the medically acceptable excipients comprise a buffer, an excipient, an isotonic agent, and / or a stabilizer; the preparation is a lyophilized powder prepared by a staged lyophilization process;

[0012] Among them, the staged freeze-drying process includes three stages:

[0013] Pre-freezing stage: cool to below -40℃ and keep warm for 120~180min;

[0014] Primary drying stage: heat to -10°C and keep warm for 480~840min;

[0015] Desorption and drying stage: The conditions of the first stage are: heating to 10℃ and keeping warm for 60~120min; the conditions of the second stage are: heating to 30℃ and keeping warm for 360~720min.

[0016] Preferably, the mass concentration of canagliflozin and semaglutide in the preparation is 1:1 to 1:5;

[0017] More preferably, the mass concentration of canagliflozin in the preparation is 0.25 mg / ml to 4 mg / ml;

[0018] The mass concentration of semaglutide in the preparation is 0.25 mg / ml~4 mg / ml.

[0019] Preferably, the buffer comprises one or more of histidine, citrate, and phosphate; wherein the citrate is sodium citrate dihydrate; and the phosphate is disodium hydrogen phosphate dihydrate.

[0020] Preferably, the concentration of histidine is 0.1-3 mg / ml;

[0021] The concentration of sodium citrate dihydrate is 0.1~8mg / ml;

[0022] The concentration of disodium hydrogen phosphate dihydrate is 0.1~7mg / ml.

[0023] Preferably, the histidine concentration is 1.5-2.5 mg / ml;

[0024] The concentration of sodium citrate dihydrate is 3.0~6.0mg / ml;

[0025] The concentration of disodium hydrogen phosphate dihydrate is 3.5~5.5mg / ml.

[0026] Preferably, the excipient includes one or more of mannitol, sucrose, and trehalose.

[0027] Preferably, the concentration of mannitol is 2.5-10 mg / ml;

[0028] The concentration of sucrose is 5-20 mg / ml;

[0029] The concentration of trehalose is 2~15mg / ml.

[0030] Preferably, the concentration of mannitol is 5-8 mg / ml;

[0031] The concentration of sucrose is 5-8 mg / ml;

[0032] The concentration of trehalose is 5~8mg / ml.

[0033] Preferably, the isotonic agent comprises sodium chloride.

[0034] Preferably, the concentration of sodium chloride is 5-8 mg / ml.

[0035] Preferably, the pH adjuster includes hydrochloric acid or sodium hydroxide.

[0036] Preferably, the stabilizer comprises poloxamer 188.

[0037] Preferably, the concentration of Poloxamer 188 is 0-2 mg / ml.

[0038] Preferably, the concentration of Poloxamer 188 is 0.5-1 mg / ml.

[0039] A second aspect of the present invention provides a method for preparing a hypoglycemic pharmaceutical preparation, the process comprising:

[0040] 1) Adding a buffer, excipient, isotonic agent and / or stabilizer to a solvent, adjusting the pH to 4.0-4.5 after dissolution, dissolving the canagliflozin API therein, and adjusting the pH to 6.0-7.0 to obtain system 1;

[0041] 2) dissolving the semaglutide API in the system 1, adjusting the pH of the solution to 6.0-7.0, fixing the volume, filtering and sterilizing, aliquoting, and lyophilizing to obtain the product;

[0042] Wherein, the freeze-drying includes three stages:

[0043] Pre-freezing stage: cool to below -40℃ and keep warm for 120~180min;

[0044] Primary drying stage: heat to -10°C and keep warm for 480~840min;

[0045] Desorption and drying stage: The conditions of the first stage are: heating to 10℃ and keeping warm for 60~120min; the conditions of the second stage are: heating to 30℃ and keeping warm for 360~720min.

[0046] Preferably, the dissolving is dissolving with water for injection.

[0047] Preferably, the filtration sterilization is performed by filtration sterilization using a 0.22 μm polyethersulfone filter.

[0048] It can be seen from the above technical solution that the technical effect achieved in the present invention is: the present invention combines the two active ingredients, semaglutide and canagliflozin, through a carefully designed prescription to form a compound preparation. The preparation adopts an advanced freeze-drying process, which not only greatly improves its overall quality, but also significantly reduces the adverse effects of temperature on the performance of the preparation. The application of this process ensures the stability of the preparation during transportation, storage and clinical use, thereby providing patients with a more reliable medication option. In addition, this innovative preparation method also effectively reduces the patient's medication cost, further enhancing its clinical application value. In summary, the present invention not only improves the technical performance of the preparation, but also provides obvious advantages in economic benefits and patient convenience, and has important clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0050] Figure 1 The accompanying drawings are actual pictures of the appearance and properties of the freeze-dried products of Examples 1, 3, 5 and 6. DETAILED DESCRIPTION

[0051] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention. Example 1

[0052] The formula of the hypoglycemic preparation is shown in Table 1 below;

[0053] Table 1

[0054]

[0055] The preparation method comprises the following steps:

[0056] 1) Water for injection as solvent;

[0057] 2) Add 1.5 mg / ml histidine, 5 mg / ml mannitol, and 8 mg / ml sodium chloride to water for injection;

[0058] 3) The pH of the solution was adjusted to 4.0 with hydrochloric acid and / or sodium hydroxide, and 2.4 mg / ml of canagliflozin API was dissolved in the solution;

[0059] 4) The pH of the solution was adjusted to 6.6 with hydrochloric acid and / or sodium hydroxide, and 2.4 mg / ml of semaglutide API was dissolved in the solution;

[0060] 5) Adjust the pH of the solution to 6.6 with hydrochloric acid and / or sodium hydroxide, and dilute to the total volume with water for injection;

[0061] 6) Filter and sterilize using a 0.22 μm polyethersulfone filter, dispense into 5 ml vials, and lyophilize.

[0062] The freeze-drying process is as follows:

[0063] The partially stoppered 5ml vials are neatly arranged and loaded into the freeze dryer. The system then rapidly cools the sample to below -40°C for a pre-freeze and maintains this temperature for 120 minutes to ensure the sample is fully frozen, paving the way for the subsequent drying step.

[0064] Next, the freeze dryer gradually raises the temperature from -40°C to -10°C over 30 minutes, entering the primary drying phase. This phase primarily aims to remove free water from the sample while maintaining its structural integrity. The primary drying process lasts 840 minutes to ensure complete evaporation of the water.

[0065] The system then enters the first stage of desorption drying, where the temperature is raised from -10°C to 10°C over 30 minutes and maintained at this temperature for 60 minutes. This stage aims to further remove bound water from the sample, ensuring that the product reaches a higher dryness standard.

[0066] Finally, the freeze dryer enters the second stage of desorption drying, where the temperature is raised from 10°C to 30°C over 30 minutes and maintained at this temperature for 360 minutes. This step thoroughly desorbs any residual moisture from the sample, ensuring the stability and long-term storage properties of the final product.

[0067] After the freeze-drying process is complete, the system automatically performs stoppering and capping operations to ensure the vial's tightness and sterility. The result is a high-quality freeze-dried preparation whose physical and chemical properties meet strict quality standards. Example 2

[0068] The formula of the hypoglycemic preparation is shown in Table 2 below;

[0069] Table 2

[0070]

[0071] The preparation method is the same as that of Example 1.

[0072] The freeze-drying process is as follows: compared with Example 1, the pre-freezing stage lasts 130 minutes; the primary drying stage lasts 500 minutes; the first stage of desorption drying lasts 70 minutes; and the second stage of desorption drying lasts 600 minutes. Example 3

[0073] The formula of the hypoglycemic preparation is shown in Table 3 below;

[0074] Table 3

[0075]

[0076] The preparation method is the same as that of Example 1.

[0077] The freeze-drying process is as follows:

[0078] The freeze-drying process is as follows: compared with Example 1, the pre-freezing stage takes 140 minutes; the primary drying stage takes 620 minutes; the first stage of desorption drying takes 90 minutes; and the second stage of desorption drying takes 400 minutes. Example 4

[0079] The formula of the hypoglycemic preparation is shown in Table 4 below;

[0080] Table 4

[0081]

[0082] The preparation method is the same as that of Example 1.

[0083] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 170 minutes; the primary drying stage takes 700 minutes; the first analytical drying stage takes 90 minutes; and the second analytical drying stage takes 700 minutes. Example 5

[0084] The formula of the hypoglycemic preparation is shown in Table 5 below;

[0085] Table 5

[0086]

[0087] The preparation method is the same as that of Example 1.

[0088] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first analytical drying stage takes 100 minutes; and the second analytical drying stage takes 460 minutes. Example 6

[0089] The formula of the hypoglycemic preparation is shown in Table 6 below;

[0090] Table 6

[0091]

[0092] The preparation method is the same as that of Example 1.

[0093] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first analytical drying stage takes 100 minutes; and the second analytical drying stage takes 460 minutes. Example 7

[0094] The formula of the hypoglycemic preparation is shown in Table 7 below;

[0095] Table 7

[0096]

[0097] The preparation method is the same as that of Example 1.

[0098] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first analytical drying stage takes 100 minutes; and the second analytical drying stage takes 460 minutes.

[0099] The formulation of the hypoglycemic preparation of Example 8 is shown in Table 8 below;

[0100] Table 8

[0101]

[0102] The preparation method is the same as that of Example 1.

[0103] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first analytical drying stage takes 100 minutes; and the second analytical drying stage takes 460 minutes. Example 9

[0104] The formula of the hypoglycemic preparation is shown in Table 9 below;

[0105] Table 9

[0106]

[0107] The preparation method is the same as that of Example 1.

[0108] The freeze-drying process is as follows: Compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first analytical drying stage takes 100 minutes; and the second analytical drying stage takes 460 minutes. Example 10

[0109] The formulation of the hypoglycemic preparation is shown in Table 10 below;

[0110] Table 10

[0111]

[0112] The preparation method is the same as that of Example 1.

[0113] The freeze-drying process is as follows: compared with Example 1, the pre-freezing stage takes 150 minutes; the primary drying stage takes 520 minutes; the first stage of desorption drying takes 100 minutes; and the second stage of desorption drying takes 460 minutes. Example 11

[0114] The formula of the hypoglycemic preparation is shown in Table 11 below;

[0115] Table 11

[0116]

[0117] The preparation method is the same as that of Example 1.

[0118] The freeze-drying process is as follows:

[0119] Compared with Example 1, the pre-freezing stage lasts for 180 minutes; the primary drying stage lasts for 480 minutes; the first analytical drying stage lasts for 120 minutes; and the second analytical drying stage lasts for 720 minutes. Example 12

[0120] The formula of the hypoglycemic preparation is shown in Table 12 below;

[0121] Table 12

[0122]

[0123] The preparation method is the same as that of Example 1.

[0124] The freeze-drying process is as follows:

[0125] Compared with Example 1, the pre-freezing stage lasts for 180 minutes; the primary drying stage lasts for 480 minutes; the first analytical drying stage lasts for 120 minutes; and the second analytical drying stage lasts for 720 minutes.

[0126] Comparative Example 1:

[0127] According to the pharmaceutical preparation disclosed in CN 115135305 A, the following canagliflozin injection and semaglutide injection were prepared:

[0128] Prepare canagliflozin injection as follows:

[0129] 1) 80% water for injection as solvent;

[0130] 2) Add 0.74 mg / ml L-glutamic acid and 24 mg / ml glycerol to water for injection;

[0131] 3) The pH of the solution was adjusted to 4.0 with hydrochloric acid and / or sodium hydroxide, and 9.6 mg / ml of canagliflozin API was dissolved in the solution;

[0132] 4) Adjust the pH of the solution to 4.0 with hydrochloric acid and / or sodium hydroxide, and dilute to the total volume with water for injection.

[0133] Prepare semaglutide injection as follows:

[0134] 1) 80% water for injection as solvent;

[0135] 2) Add 1.55 mg / ml L-histidine, 5.34 mg / ml disodium hydrogen phosphate dihydrate, and 6.4 mg / ml sodium chloride to water for injection;

[0136] 3) The pH of the solution was adjusted to 7.0 with hydrochloric acid and / or sodium hydroxide, and 4.8 mg / ml of semaglutide API was dissolved in the solution;

[0137] 4) Adjust the pH of the solution to 7.0 with hydrochloric acid and / or sodium hydroxide, and dilute to the total volume with water for injection.

[0138] Before use, mix 0.25 ml of canagliflozin injection and 0.5 ml of semaglutide injection, that is, the dosage of canagliflozin is 2.4 mg and the dosage of semaglutide is 2.4 mg.

[0139] Comparative Example 2:

[0140] According to the pharmaceutical preparation disclosed in CN 118382451 A, the following liquid pharmaceutical preparation containing canagliflozin and semaglutide was prepared:

[0141] 1) 80% water for injection as solvent;

[0142] 2) Add 6mM histidine, 20mg / ml sorbitol, 0.05mg / ml polysorbate 80 and 15% w / v hydroxypropyl β-cyclodextrin (Gangwal ® Gangwal Healthcare Pvt Ltd. (average MS: 0.68, MS range: 0.40-1.50) 1 Dissolve in water for injection;

[0143] 3) The pH of the solution was adjusted to 5.8 with hydrochloric acid and / or sodium hydroxide, and 3.2 mg / ml of canagliflozin API and 3.2 mg / ml of semaglutide API were dissolved in the above solution;

[0144] 4) Adjust the pH of the solution to 5.8 with hydrochloric acid and / or sodium hydroxide, and dilute to the total volume with water for injection.

[0145] Note: 1 MS: molar substitution, corresponding to hydroxypropyl groups per glucose unit.

[0146] Comparative Example 3:

[0147] Compared with the prescription of Example 1, the prescription of Comparative Example 3 is based on polysorbate 80 and hydroxypropyl β-cyclodextrin (Gangwal ® Gangwal Healthcare Pvt Ltd.) (average MS: 0.68, MS range: 0.40-1.50) replaced mannitol and histidine in Example 1 as shown in Table 13 below;

[0148] Table 13

[0149]

[0150] The preparation method is the same as that of Example 1.

[0151] The freeze-drying process is the same as in Example 1.

[0152] Examples 1 to 12 and Comparative Examples 1 to 3 were tested at 2 to 8°C for 6 months, using pH, osmotic pressure molar concentration (mOsmol / kg), related substances, and high molecular weight substances as indicators, and compared with the comparative examples. The test results are shown in Table 14 below:

[0153] Table 14

[0154]

[0155] Examples 1 to 12 and Comparative Examples 1 to 3 were tested at 25°C for 6 months, using pH, osmotic pressure molar concentration (mOsmol / kg), related substances and high molecular weight substances as indicators, and compared with the comparative examples. The test results are shown in Tables 15 and 16:

[0156] Table 15

[0157]

[0158] Table 16

[0159]

[0160] The above results demonstrate that the freeze-dried pharmaceutical compositions of semaglutide and canagliflozin and their preparation methods provided herein effectively improve the temperature resistance of semaglutide and canagliflozin, thereby extending their shelf life at room temperature. The finished formulations of each example exhibited significant advantages over the comparative example in terms of pH, osmolality (mOsmol / kg), related substances, and high-molecular-weight substances. No significant differences were observed between Examples 1, 2, 4, 5, 7, 8, 10, and 11. However, since the staged freeze-drying process was not used in Comparative Examples 1 and 2, the maximum single impurity and total impurity contents increased significantly after being placed for 6 months, and the difference was significant compared with the example group; in Comparative Example 3, polysorbate 80 and hydroxypropyl β-cyclodextrin were used to replace histidine and mannitol, and after being placed for 6 months, the maximum single impurity and total impurity contents also increased to a certain extent. It can be seen that the freeze-dried pharmaceutical composition of semaglutide and canagliflozin and the preparation method thereof of the present invention improve the adverse effects of the preparation on high temperature, and the preparation quality stability is excellent, which greatly improves the stability of the preparation during transportation, storage and use, and has obvious clinical advantages. The freeze-dried samples of Examples 1, 3, 5 and 6 are as follows. Figure 1 shown.

[0161] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0162] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A hypoglycemic pharmaceutical preparation, comprising semaglutide, canagliflozin, a buffer, an excipient, an isotonic agent, and poloxamer 188, wherein the drug mass concentration ratio of canagliflozin to semaglutide in the preparation is 1:1 to 1:5, and the pharmaceutical preparation is a freeze-dried powder prepared by a staged freeze-drying process, wherein the staged freeze-drying process comprises three stages: a pre-freezing stage: cooling to below -40°C and keeping warm for 120 to 180 minutes; a primary drying stage: heating to -10°C and keeping warm for 480 to 840 minutes; an analytical drying stage: the conditions of the first stage are: heating to 10°C and keeping warm for 60 to 120 minutes; and the conditions of the second stage are: heating to 30°C and keeping warm for 360 to 720 minutes.

2. A hypoglycemic pharmaceutical preparation according to claim 1, characterized in that: The buffer comprises one or more of histidine, citrate, and phosphate; wherein the citrate is sodium citrate dihydrate; and the phosphate is disodium hydrogen phosphate dihydrate.

3. A hypoglycemic pharmaceutical preparation according to claim 2, characterized in that: The concentration of histidine is 0.1~3 mg / ml; the concentration of sodium citrate dihydrate is 0.1~8 mg / ml; and the concentration of disodium hydrogen phosphate dihydrate is 0.1~7 mg / ml.

4. A hypoglycemic pharmaceutical preparation according to claim 3, characterized in that: The concentration of histidine is 1.5~2.5 mg / ml; the concentration of sodium citrate dihydrate is 3.0~6.0 mg / ml; and the concentration of disodium hydrogen phosphate dihydrate is 3.5~5.5 mg / ml.

5. The hypoglycemic pharmaceutical preparation according to claim 1, characterized in that: The excipients include one or more of mannitol, sucrose, and trehalose.

6. The hypoglycemic pharmaceutical preparation according to claim 5, characterized in that: The concentration of mannitol is 2.5~10 mg / ml; the concentration of sucrose is 5~20 mg / ml; and the concentration of trehalose is 2~15 mg / ml.

7. The hypoglycemic pharmaceutical preparation according to claim 6, characterized in that: The concentration of mannitol is 5~8 mg / ml; the concentration of sucrose is 5~8 mg / ml; and the concentration of trehalose is 5~8 mg / ml.

8. The hypoglycemic pharmaceutical preparation according to claim 1, characterized in that: The isotonic agent includes sodium chloride, and its concentration is 5-8 mg / ml.

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