Smeglutide suppository and preparation method thereof

Abstract

The invention provides a semeglutide suppository and a preparation method thereof. The semeglutide suppository provided by the invention is stable in quality and high in bioavailability, and also has the characteristics of rapid drug release and continuous drug administration.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and specifically relates to a semaglutide suppository and a preparation method thereof. Background Art

[0002] Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that can bind to and activate the GLP-1 receptor. By mediating the GLP-1 receptor, it stimulates insulin secretion in a glucose-dependent manner and reduces glucagon secretion, thereby achieving the effect of lowering blood sugar.

[0003] Semaglutide was originally developed by the Danish pharmaceutical company Novo Nordisk. Semaglutide injection was first approved by the FDA in December 2017 under the trade name Ozempic for blood sugar control in type 2 diabetes. In September 2019, the FDA approved semaglutide oral tablets under the trade name Rybelsus, also for blood sugar control in type 2 diabetes. In June 2021, the FDA approved semaglutide injection for a third time under the trade name Wegovy for weight loss.

[0004] However, semaglutide injection is inconvenient to administer and can easily cause side effects such as rash at the injection site, nausea, and loss of appetite. The subsequently developed semaglutide oral tablets also suffer from low bioavailability, significant food sensitivity, and significant individual variability.

[0005] Therefore, there is an urgent need to develop new dosage forms of semaglutide that have high bioavailability and are easy to administer. Summary of the Invention

[0006] In response to the above problems, after repeated exploration, the inventors of the present application developed a new dosage form of semaglutide - suppository and a preparation method thereof.

[0007] Specifically, this application provides the following technical solutions:

[0008] In a first aspect, the present application provides a semaglutide suppository comprising the following components by weight: 2 to 10 parts of semaglutide; 20 to 50 parts of a solubilizer; 20 to 60 parts of an absorption enhancer; 5 to 20 parts of a surfactant; and 40 to 60 parts of a base.

[0009] In a second aspect, the present application provides a method for preparing the semaglutide suppository according to the first aspect, comprising the following steps: obtaining a mixture of a solubilizer, an absorption enhancer, semaglutide, a base and a surfactant, stirring and dissolving the mixture, and cooling and shaping the mixture in a mold.

[0010] This application uses a heating dissolution method to prepare semaglutide suppositories. Single-factor experiments were performed to screen the type and dosage of surfactants and the duration of ultrasonic stirring. The formulation process of semaglutide suppositories was optimized using the star-point response surface methodology to determine the optimal formulation process and verify the optimal formulation.

[0011] The quality, stability and other indicators of the semaglutide suppositories prepared in this application are in compliance with the relevant provisions of the General Rules for Preparations (0107) of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0012] The semaglutide suppositories provided in this application are stable in all aspects and meet the requirements of drug administration. The absorption enhancer identified through screening significantly improves bioavailability. Furthermore, the semaglutide suppositories provided in this application offer rapid drug release and sustained drug delivery, making administration convenient and avoiding gastrointestinal irritation. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 This is the drug-time curve obtained by LC-MS / MS analysis of the plasma of beagle dogs in the rectal suppository administration group in Example 4. Figure 2 This is the drug-time curve obtained by LC-MS / MS analysis of the plasma of beagle dogs in the intravenous drug administration group in Example 4. Figure 3 This is the drug-time curve obtained by LC-MS / MS analysis of the plasma of beagle dogs in the oral drug administration group in Example 4. DETAILED DESCRIPTION

[0013] This application aims to research and develop the formulation and preparation process of semaglutide suppositories, establish quality research methods, investigate the stability of suppositories under different conditions, and conduct preliminary comparative pharmacokinetic studies in beagle dogs.

[0014] In the screening of semaglutide suppository prescriptions, the present application screened the base, absorption enhancer, surfactant and solubilizer.

[0015] 1. Matrix and preparation method thereof

[0016] The matrix that can be used for the semaglutide suppository provided in this application is selected from:

[0017] 1.1 Glycerol gelatin matrix

[0018] Specifically, the glycerol-gelatin matrix is ​​prepared as follows: 2.0 g of gelatin is placed in an evaporating dish of known weight. An appropriate amount of distilled water is added and the dish is allowed to soak for 30 minutes to allow it to swell and soften. Excess water is then drained. 7.0 g of glycerol is added and heated in a water bath to dissolve the gelatin. Continue heating until the desired weight is reached, resulting in 10.0 g of a glycerol-gelatin matrix (glycerol:gelatin:water = 7:2:1).

[0019] 1.2 Water-soluble matrix

[0020] The water-soluble matrix is ​​a combination of polyethylene glycol series excipients in different proportions, such as: taking 7.0 g of polyethylene glycol PEG6000 into an evaporating dish of known weight, heating in a water bath to melt; then adding 3.0 g of PEG400, heating and stirring evenly in a water bath to prepare 10.0 g of a water-soluble matrix (PEG6000:PEG400=7:3).

[0021] Proportion Melting point PEG-1500 40-41 PEG-4000(50%)+PEG-300(50%) 40-41 PEG-4000(20%)+PEG-1500(80%) 42-43 PEG-4000(25%)+PEG-1500(75%) 43.5-44.5 PEG-4000(30%)+PEG-1500(70%) 44.5-46 PEG-4000(40%)+PEG-1500(60%) 47

[0022] 1.3 Fatty Matrix

[0023] Specifically, the fatty matrix was prepared as follows: 1.3 g of beeswax, 8.3 g of peanut oil, 0.3 g of lanolin, and 0.1 g of gum arabic were placed in an evaporating dish of known weight, and heated in a water bath to melt all of them to prepare 10.0 g of the fatty matrix.

[0024] 1.4 Oil-in-water (O / W) emulsion matrix

[0025] Specifically, the preparation method of an oil-in-water (O / W) emulsion matrix is ​​as follows: 3.0 g of stearic acid, 0.8 g of glyceryl monostearate, and 1.0 g of lanolin, the oil phase components, are placed in an evaporating dish of known weight, heated in a 60°C water bath until completely melted, and kept warm; 0.2 g of triethanolamine, 3.8 g of propylene glycol, and 1.2 g of Tween-80, the aqueous phase components, are placed in a beaker, and heated in a 60°C water bath to a temperature equal to or slightly higher than that of the oil phase; the aqueous phase is slowly dripped into the oil phase in the water bath, stirring uniformly in the same direction as dripping, to prepare 10.0 g of the O / W emulsion matrix.

[0026] 2. Absorption enhancers

[0027] The absorption promoter that can be used for the semaglutide suppository provided in the present application is selected from one or more of the following: C10 (sodium decanoate), SNAC (sapropel sodium), C8 (sodium octanoate), 5-CNAC (8-(N-2-hydroxy-5-chloro-benzoyl)-aminocaprylate), 4-CNAB (N-(4-chlorosalicyloyl)-4-aminobutyrate), SNAD (n-(10-[2-hydroxybenzoyl-]amino)decanoic acid monosodium salt), NAC (8-n-(2-hydroxybenzoyl)aminocaprylate), NAD (1-n-(2-hydroxybenzoyl)aminocaprylate). acyl) aminodecanoic acid), 4-MOAC (8-n-(2-hydroxy-4-methoxybenzoyl) aminooctanoic acid) and its salts, sodium hexanoate, sodium heptanoate, sodium nonanoate, sodium oleate, 4-[(5-chloro-2-hydroxybenzoyl) amino] butyric acid and its salts, 6-(5-bromo-2-hydroxybenzamido) hexanoic acid and its salts, 7-[(5-chloro-2-hydroxyphenyl) formamido] heptanoic acid and its salts, 6-[(5-chloro-2-hydroxybenzoyl) amino] hexanoic acid and its salts, 5-[(5-chloro-2-hydroxybenzoyl) amino] - pentanoic acid and its salts, and sodium tetradecyl sulfate.

[0028] 3. Surfactants

[0029] The surfactants that can be used in the semaglutide suppositories provided herein are selected from one or more of the following: nonionic surfactants (Tween-80, Span-40, Poloxamer-188) and anionic surfactants (sodium lauryl sulfate, sodium lauryl sulfonate, etc.).

[0030] 4. Solubilizer

[0031] The solubilizer that can be used in the semaglutide suppository provided in the present application is selected from one or more of the following: water-soluble excipients, such as water, ethanol, propylene glycol, glycerol, PEG400, etc.

[0032] The method for preparing semaglutide suppositories provided in the present application adopts a hot melt method, which specifically comprises the following steps: weighing a prescribed amount of a solubilizer and an absorption enhancer, heating and stirring to dissolve them; weighing a prescribed amount of semaglutide, adding it to the above-mentioned mixed solution, and stirring to dissolve it; preparing the required suppository base as described above, weighing a prescribed amount of the base, adding it to the above-mentioned mixed solution, and stirring to dissolve it; weighing a prescribed amount of a surfactant, adding it to the above-mentioned mixed solution, and stirring to dissolve it; adjusting the pH value to neutral with hydrochloric acid or sodium hydroxide aqueous solution; and injecting it into a lubricant-coated suppository mold while it is hot, solidifying and demolding it to prepare the suppository.

[0033] This application optimizes the preparation method of semaglutide suppositories from the following aspects:

[0034] 1. Stirring method

[0035] Hot melt method was used to prepare suppositories. The effects of pure stirring, pure ultrasound and ultrasound plus stirring on the preparation of suppositories were investigated with the appearance and uniformity of the suppositories as indicators.

[0036] 2. Investigation of stirring temperature

[0037] The effect of stirring temperature on the preparation of suppositories was investigated using solution fluidity and suppository appearance as indicators.

[0038] 3. Investigation of cooling temperature and time

[0039] The preparation of suppositories at different temperatures, the time required for suppository formation, and the appearance and properties of the suppositories were investigated.

[0040] Specifically, this application provides the following technical solutions:

[0041] In one aspect, the present application provides a semaglutide suppository comprising the following components by weight: 2 to 10 parts of semaglutide; 20 to 50 parts of a solubilizer; 20 to 60 parts of an absorption enhancer; 5 to 20 parts of a surfactant; and 40 to 60 parts of a base.

[0042] In a specific embodiment, the semaglutide suppository comprises the following components in parts by weight: 2 to 7 parts of semaglutide; 20 to 40 parts of a solubilizer; 40 to 60 parts of an absorption enhancer; 5 to 20 parts of a surfactant; and 40 to 60 parts of a base.

[0043] In a specific embodiment, the semaglutide suppository comprises the following components by weight: 4 parts of semaglutide; 40 parts of solubilizer; 50 parts of absorption enhancer; 20 parts of surfactant; and 50 parts of base.

[0044] In a specific embodiment, the solubilizing agent is selected from one or more of the following: water, ethanol, propylene glycol, glycerol and PEG400.

[0045] In a specific embodiment, the solubilizing agent is a mixture of water and any one selected from ethanol, propylene glycol and glycerol.

[0046] In a specific embodiment, the weight ratio of water to ethanol, propylene glycol or glycerol is 1:(1-3).

[0047] In a specific embodiment, the absorption enhancer is an organic acid and its ester or salt.

[0048] In a specific embodiment, the absorption enhancer is selected from one or more of the following: sodium decanoate, sapropel sodium, sodium octanoate, 8-(N-2-hydroxy-5-chloro-benzoyl)-aminocaprylate, N-(4-chlorosalicyloyl)-4-aminobutyrate, n-(10-[2-hydroxybenzoyl-]amino)decanoic acid monosodium salt, 8-n-(2-hydroxybenzoyl)aminocaprylate, 10-n-(2-hydroxybenzoyl)aminodecanoic acid, 8-n-(2-hydroxybenzoyl)aminocaprylate, 10-n-(2-hydroxybenzoyl)aminodecanoic acid, 8-n-(2-hydroxy-4-methyl benzoyl)amino caprylic acid and its salts, sodium hexanoate, sodium heptanoate, sodium nonanoate, sodium oleate, 4-[(5-chloro-2-hydroxybenzoyl)amino]butyric acid and its salts, 6-(5-bromo-2-hydroxybenzamido)hexanoic acid and its salts, 7-[(5-chloro-2-hydroxyphenyl)formamido]heptanoic acid and its salts, 6-[(5-chloro-2-hydroxybenzoyl)amino]hexanoic acid and its salts, 5-[(5-chloro-2-hydroxybenzoyl)amino]-pentanoic acid and its salts, and sodium tetradecyl sulfate.

[0049] In specific embodiments, the surfactant is a nonionic surfactant or an anionic surfactant.

[0050] In a specific embodiment, the surfactant is selected from one or more of the following: Tween-80, Span-40, Poloxamer-188, sodium lauryl sulfate, and sodium lauryl sulfonate.

[0051] In specific embodiments, the matrix is ​​a glycerol gelatin matrix, a water-soluble matrix, a fatty matrix, or an oil-in-water emulsion matrix.

[0052] In a specific embodiment, the glycerol gelatin matrix comprises glycerol, gelatin, and water in a weight ratio of 7:2:1.

[0053] In a specific embodiment, the water-soluble matrix is ​​polyethylene glycol.

[0054] In specific embodiments, the water-soluble matrix comprises PEG6000 and PEG400 in a weight ratio of 7:3, PEG4000 and PEG400 in a weight ratio of 1:1, or PEG4000 and PEG1500 in a weight ratio of 1:3.

[0055] In a specific embodiment, the fatty matrix is ​​beeswax, peanut oil, lanolin and gum arabic in a weight ratio of 13:83:3:1.

[0056] In a specific embodiment, the oil-in-water emulsion base includes stearic acid, glyceryl monostearate and lanolin in a weight ratio of 3:0.8:1 as oil phase components, and triethanolamine, propylene glycol and Tween-80 in a weight ratio of 2:38:12 as water phase components.

[0057] On the other hand, the present application provides a method for preparing semaglutide suppositories, comprising the following steps: obtaining a mixture of 20 to 50 parts by weight of a solubilizer, 20 to 60 parts by weight of an absorption enhancer, 2 to 10 parts by weight of semaglutide, 40 to 60 parts by weight of a base and 5 to 20 parts by weight of a surfactant, stirring and dissolving the mixture, and cooling and shaping the mixture in a mold.

[0058] In a specific embodiment, the method for preparing semaglutide suppositories comprises the following steps: obtaining a mixture of 20 to 40 parts by weight of a solubilizer, 40 to 60 parts by weight of an absorption enhancer, 2 to 7 parts by weight of semaglutide, 40 to 60 parts by weight of a base, and 5 to 20 parts by weight of a surfactant, stirring and dissolving the mixture, and cooling and shaping the mixture in a mold.

[0059] In a specific embodiment, the stirring is ultrasonic stirring.

[0060] In a specific embodiment, the stirring is performed at a temperature of 50°C to 55°C.

[0061] In a specific embodiment, the cooling is performed at -2°C to 4°C for 10 to 40 minutes.

[0062] In a specific embodiment, the cooling is performed at -2°C for 10 to 15 minutes.

[0063] In a specific embodiment, the method for preparing semaglutide suppositories provided herein comprises the following steps: 1) dissolving 20 to 50 parts by weight of a solubilizer and 20 to 60 parts by weight of an absorption enhancer by ultrasonic stirring at a temperature of 50° C. to 55° C.; 2) adding 2 to 10 parts by weight of semaglutide to the mixed solution of step 1), and continuing to ultrasonically stir at a temperature of 50° C. to 55° C. to dissolve it; 3) adding 40 to 60 parts by weight of a base to the mixed solution of step 2), and continuing to ultrasonically stir at a temperature of 50° C. to 55° C. to dissolve it; 4) adding 5 to 20 parts by weight of a surfactant to the mixed solution of step 3), and continuing to ultrasonically stir at a temperature of 50° C. to 55° C. to dissolve it; and 5) pouring into a mold and cooling at -2° C. to 4° C. for 10 to 40 minutes to prepare a suppository.

[0064] Example

[0065] The following examples are provided to illustrate the present invention but are not intended to limit the scope of the present invention. Any modification or substitution of the methods, steps, or conditions of the present invention without departing from the spirit and substance of the present invention shall fall within the scope of the present invention.

[0066] Unless otherwise specified, the reagents used in the examples are conventional commercially available reagents, and the technical means used in the examples are conventional means well known to those skilled in the art.

[0067] Example 1 Study on the Prescription Process of Semaglutide Suppositories

[0068] This example provides a study on the formulation and process of semaglutide suppositories.

[0069] The formulation of semaglutide suppository was designed, as shown in Table 1 below.

[0070] Table 1

[0071]

[0072]

[0073] The suppository is prepared by the hot melt method. The specific preparation method is as follows:

[0074] Accurately weigh the prescribed amount of absorption enhancer and surfactant that have passed through a 100-mesh sieve and set aside. Weigh the prescribed amount of matrix into a beaker and heat the beaker in a 60°C water bath. After the matrix melts, add the absorption enhancer and surfactant and stir continuously until they are dissolved. Keep warm in a 60°C water bath.

[0075] Weigh the semaglutide sample, dissolve it in a solubilizer, and add it to the prepared matrix while stirring. Stir evenly and adjust the pH to neutral with hydrochloric acid or sodium hydroxide solution. While hot, inject it into a lubricated suppository mold and solidify at -2°C to 2°C. De-mold the suppository and absorb the moisture from the surface with absorbent paper to obtain the suppository sample.

[0076] The stirring mode, stirring temperature, cooling temperature and time in the preparation method were investigated, as follows.

[0077] 1. Investigation of stirring method

[0078] Suppositories were prepared by hot melt method. The effects of pure stirring, pure ultrasound and ultrasound plus stirring on the preparation of suppositories were investigated with the appearance and uniformity of the suppositories as indicators. The results are shown in Table 2.

[0079] Table 2

[0080]

[0081] As can be seen, suppositories prepared using ultrasound plus stirring exhibited good formability, a smooth, non-porous surface, uniform color distribution, and moderate hardness. Suppositories prepared using ultrasound plus stirring were examined for uniformity, melting time, and dissolution, and the results showed that all met the requirements with no significant differences. Therefore, ultrasound plus stirring was adopted for the preparation of suppositories.

[0082] 2. Investigation of stirring temperature

[0083] The effects of different stirring temperatures on the preparation of suppositories were investigated using the fluidity of the solution and the appearance of the suppositories as indicators. The results are shown in Table 3.

[0084] Table 3

[0085]

[0086] The results showed that suppositories prepared at 50-55°C were the best. The homogeneity, melting time, and dissolution of suppositories prepared at temperatures between 50-55°C were examined, and the results showed that all met the requirements with no significant differences. Therefore, the stirring temperature was controlled between 50-55°C.

[0087] 3. Investigation of cooling temperature and time

[0088] The preparation of suppositories at temperatures of -20°C, -2°C, 4°C, and 10°C was investigated, as were the time required for suppository formation and the appearance of the suppositories. The results are shown in Table 4.

[0089] Table 4

[0090]

[0091] The results showed that the appearance of the suppositories was best when cooled at -2°C and 4°C. Since the cooling time at 4°C was too long, the cooling temperature of -2°C and the cooling time of about 15 minutes were selected.

[0092] Example 2 Quality Study of Semaglutide Suppositories

[0093] In this example, the semaglutide suppositories prepared in Example 1 were studied in terms of appearance, weight difference, melting time, content, etc., in accordance with the provisions of the summary quality inspection of suppositories in the General Rules for Preparations (0107) of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0094] The results are shown in Table 5.

[0095] Table 5

[0096]

[0097]

[0098] Example 3 Stability Study of Semaglutide Suppositories

[0099] Using appearance, content, melting time, and dissolution rate as evaluation indicators, the effects of temperature, humidity, and light on the stability of semaglutide suppositories were investigated through influencing factor experiments.

[0100] 1. High temperature test

[0101] An appropriate amount of semaglutide suppositories (prescription 15) prepared in Example 1 were placed in 5 mL EP tubes, placed in a clean watch glass, and placed in a vacuum drying oven at 40°C for 10 days. Samples were taken on days 0, 5, and 10, and the appearance, properties, related substances, and contents of the suppositories were examined. The results are shown in Table 6.

[0102] Table 6

[0103]

[0104]

[0105] As shown in Table 6, the suppositories prepared in this application all melted and deformed at high temperatures, resulting in a decrease in the content of the main drug, semaglutide, and an increase in the total number of related impurities. Because the suppositories melted and deformed at high temperatures, dissolution and melting time were not investigated.

[0106] 2. High humidity test

[0107] An appropriate amount of semaglutide suppositories (Formulation 15) prepared in Example 1 were placed in 5 mL EP tubes, placed in clean watch glasses, and placed in a sealed container maintained at a constant temperature and humidity of 92.5% at room temperature. Samples were collected on days 0, 5, and 10 to assess the suppositories' appearance, related substances, content, dissolution, and melting time. The results are shown in Table 7.

[0108] Table 7

[0109] Inspection items 0 days 5 days 10 days Appearance Milky white, torpedo type Appearance and color remain unchanged Appearance unchanged, color yellowed content 98.83％ 98.61％ 98.39％ Related substances 0.69％ 0.91％ 1.20％ Dissolution 98.37％ 98.09％ 97.84％ Moisture absorption and weight gain —— 0.13％ 0.19％ Transformation Time Limit Comply with regulations Comply with regulations Comply with regulations

[0110] As shown in Table 7, the color of semaglutide suppositories turned yellow at a humidity of 92.5%. The content did not change significantly, and the total amount of related impurities increased slightly. The dissolution rate did not change significantly, and the melting time did not change significantly.

[0111] 3. Lighting test

[0112] An appropriate amount of semaglutide suppositories (prescription 15) prepared in Example 1 were placed in 5 mL EP tubes, placed uniformly in clean watch glasses, and placed in a light test chamber under a light intensity of 4500 ± 500 Lx for 10 days. Samples were taken on days 0, 5, and 10, and the appearance, related substances, content, dissolution, and melting time of the suppositories were examined. The results are shown in Table 8.

[0113] Table 8

[0114] Inspection items 0 days 5 days 10 days Appearance Milky white, torpedo type Appearance and color remain unchanged Appearance unchanged, color yellowed content 98.83％ 97.49％ 95.92％ Related substances 0.69％ 1.98％ 3.61％ Dissolution 98.37％ 97.08％ 95.66％ Transformation time limit Comply with regulations Comply with regulations Comply with regulations

[0115] As shown in Table 8, under light conditions, the color of semaglutide suppositories turned yellow, the semaglutide content decreased, and the total impurities of related substances increased. As the light exposure time increased, the dissolution rate of semaglutide gradually slowed down.

[0116] Example 4 Pharmacokinetic Study of Semaglutide Suppositories

[0117] This example establishes a method for detecting the blood concentration of semaglutide in vivo using LC-MS / MS, as follows.

[0118]

[0119] Liquid phase gradient elution procedure: pre-equilibrate the column with the starting mobile phase for 15 min before injection.

[0120]

[0121]

[0122]

[0123] Healthy beagle dogs were given semaglutide suppositories (prescription 15) prepared in Example 1, the original semaglutide tablets (semaglutide tablets (trade name) ), purchased from Novo Nordisk) and injection (semaglutide injection (trade name ), purchased from Novo Nordisk, the blood samples from different administration routes were processed, and the pharmacokinetic data were compared and analyzed using the established LC-MS / MS method, as follows.

[0124] 1. Suppository rectal administration group, 1 group in total, 6 beagle dogs in each group (numbered 1# to 6# respectively), 3 males and 3 females, dosage: single suppository 2 mg / kg, single rectal administration. Fast for 24 hours before administration and empty the stool. After administration, pay attention to observe whether there is discharge. If there is discharge within 1 hour, give another dose. Eat 4 hours after administration. Venous blood collection, blood collection time: 11 points within 24 hours, 0 hour before administration, 0.5, 1.5, 2, 4, 6, 8, 10, 24, 48, 72 hours after administration. EDTA anticoagulation (do not use heparin), centrifuge to obtain supernatant plasma.

[0125] The plasma was analyzed by LC-MS / MS. The average blood drug concentration results are shown in Table 9. The drug-time curve is shown in Figure 1 The pharmacokinetic parameters are shown in Table 10.

[0126] Table 9

[0127]

[0128] Table 10

[0129]

[0130]

[0131] 2. Intravenous administration group: 1 group, 6 beagle dogs (numbered 1# to 6#), 3 males and 3 females per group. Dosage: 2 mg / kg per single caudal vein injection. Venous blood was collected at 11 points within 24 hours: 0 hour before dosing and 0.5, 1.5, 2, 4, 6, 8, 10, 24, 48, and 72 hours after dosing. EDTA anticoagulation (do not use heparin) was used, and the supernatant plasma was collected by centrifugation.

[0132] The plasma was analyzed by LC-MS / MS. The average blood drug concentration results are shown in Table 11. The drug-time curve is shown in Figure 2 The pharmacokinetic parameters are shown in Table 12.

[0133] Table 11

[0134]

[0135] Table 12

[0136]

[0137]

[0138] 3. Oral administration group: 1 group, 6 beagle dogs (numbered 1# to 6#), 3 males and 3 females per group. Dosage: single oral gavage of 2 mg / kg. Fast for 24 hours before administration. Feed 4 hours after administration. Venous blood was collected at 11 points within 24 hours: 0 hour before administration and 0.5, 1.5, 2, 4, 6, 8, 10, 24, 48, and 72 hours after administration. Anticoagulant: EDTA (do not use heparin), and supernatant plasma was collected by centrifugation.

[0139] The plasma was analyzed by LC-MS / MS. The average blood drug concentration results are shown in Table 13. The drug-time curve is shown in Figure 3 The pharmacokinetic parameters are shown in Table 14.

[0140] Table 13

[0141]

[0142] Table 14

[0143]

[0144]

[0145] The absolute bioavailability was calculated according to the above table: absolute bioavailability of suppository (0-t): F% = AUC(0-t)_D suppository / AUC(0-t)_D intravenous × 100% = 7431.04 / 89193.31 × 100% = 8.33%; absolute bioavailability (0-t) after oral administration: F% = AUC(0-t)_D oral / AUC(0-t)_D intravenous × 100% = 967.69 / 89193.31 × 100% = 1.08%.

[0146] The present application has been described in detail above using general instructions and specific implementation plans, and these modifications or improvements made on the basis of the present application without departing from the spirit of the present application are all within the scope of protection required by the present application.

Claims

1. A semaglutide suppository comprising the following components in parts by weight: 2 to 10 parts of semaglutide; 20 to 50 parts of solubilizer; 20 to 60 parts of absorption enhancer; 5 to 20 parts of surfactant; and 40 to 60 parts of base.

2. The semaglutide suppository according to claim 1, comprising the following components in parts by weight: 2 to 7 parts of semaglutide; 20 to 40 parts of solubilizer; 40 to 60 parts of absorption enhancer; 5 to 20 parts of surfactant; and 40 to 60 parts of base.

3. The semaglutide suppository according to claim 1 or 2, comprising the following components in parts by weight: 4 parts of semaglutide; 40 parts of solubilizer; 50 parts of absorption enhancer; 20 parts of surfactant; and 50 parts of base.

4. The semaglutide suppository according to any one of claims 1 to 3, wherein the solubilizer is selected from one or more of the following: water, ethanol, propylene glycol, glycerol and PEG400; Preferably, the solubilizer is a mixture of water and any one selected from ethanol, propylene glycol and glycerol; More preferably, the weight ratio of water to ethanol, propylene glycol or glycerol is 1:(1-3).

5. The semaglutide suppository according to any one of claims 1 to 4, wherein the absorption enhancer is an organic acid and an ester or salt thereof; Preferably, the absorption enhancer is selected from one or more of the following: sodium decanoate, sodium sapropel, sodium octanoate, 8-(N-2-hydroxy-5-chloro-benzoyl)-aminocaprylate, N-(4-chlorosalicyloyl)-4-aminobutyrate, n-(10-[2-hydroxybenzoyl-]amino)decanoic acid monosodium salt, 8-n-(2-hydroxybenzoyl)aminocaprylate, 10-n-(2-hydroxybenzoyl)aminodecanoic acid, 8-n-(2-hydroxybenzoyl)aminocaprylate, 10-n-(2-hydroxybenzoyl)aminodecanoic acid, 8-n-(2-hydroxy-4-methoxybenzoyl) benzoyl)amino]butyric acid and its salts, 6-(5-bromo-2-hydroxybenzamido)hexanoic acid and its salts, 7-[(5-chloro-2-hydroxyphenyl)formamido]heptanoic acid and its salts, 6-[(5-chloro-2-hydroxybenzoyl)amino]hexanoic acid and its salts, 5-[(5-chloro-2-hydroxybenzoyl)amino]-pentanoic acid and its salts, and sodium tetradecyl sulfate.

6. The semaglutide suppository according to any one of claims 1 to 5, wherein the surfactant is a nonionic surfactant or an anionic surfactant; Preferably, the surfactant is selected from one or more of the following: Tween-80, Spam-40, Poloxamer-188, sodium lauryl sulfate and sodium lauryl sulfonate.

7. The semaglutide suppository according to any one of claims 1 to 6, wherein the matrix is ​​a glycerin gelatin matrix, a water-soluble matrix, a fat matrix or an oil-in-water emulsion matrix; Preferably, the glycerol gelatin matrix comprises glycerol, gelatin and water in a weight ratio of 7:2:1; Preferably, the water-soluble matrix is ​​polyethylene glycol; more preferably, the water-soluble matrix comprises PEG6000 and PEG400 in a weight ratio of 7:3, PEG4000 and PEG400 in a weight ratio of 1:1, or PEG4000 and PEG1500 in a weight ratio of 1:3; Preferably, the fatty matrix is ​​beeswax, peanut oil, lanolin and gum arabic in a weight ratio of 13:83:3:1; and / or Preferably, the oil-in-water emulsion base comprises stearic acid, glyceryl monostearate and lanolin in a weight ratio of 3:0.8:1 as oil phase components, and triethanolamine, propylene glycol and Tween-80 in a weight ratio of 2:38:12 as water phase components.

8. A method for preparing the semaglutide suppository according to any one of claims 1 to 7, comprising the following steps: A mixture comprising a solubilizer, an absorption enhancer, semaglutide, a base and a surfactant is obtained, stirred to dissolve, and cooled in a mold to set the shape.

9. The method of claim 8, wherein the stirring is ultrasonic stirring; Preferably, the stirring is carried out at a temperature of 50°C to 55°C; and / or Preferably, the cooling is performed at -2°C to 4°C for 10 to 40 minutes; More preferably, the cooling is performed at -2°C for 10 to 15 minutes.

10. The method according to claim 8 or 9, comprising the steps of: 1) dissolving the solubilizer and absorption enhancer by ultrasonic stirring at a temperature of 50° C. to 55° C.; 2) adding semaglutide to the mixed solution of step 1) and continuing ultrasonic stirring at a temperature of 50° C. to 55° C. to dissolve it; 3) adding the matrix to the mixed solution of step 2) and continuing ultrasonic stirring at a temperature of 50° C. to 55° C. to dissolve it; 4) adding a surfactant to the mixed solution of step 3) and continuing ultrasonic stirring at a temperature of 50° C. to 55° C. to dissolve the surfactant; and 5) Pour the mixture into a mold and cool at -2°C to 4°C for 10 to 40 minutes to prepare a suppository.

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