Pharmaceutical composition of semeglutide as well as preparation method and application of pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition of semeglutide as well as a preparation method and application of the pharmaceutical composition. The invention specifically provides a pharmaceutical composition, which comprises an active substance X and a pharmaceutical adjuvant A. The active substance X is semeglutide or a pharmaceutically acceptable salt thereof; the pharmaceutic adjuvant A is a diketopiperazine compound as shown in a formula I or a pharmaceutically acceptable salt thereof. The composition of the semeglutide has one or more of the following advantages that the bioavailability is higher than that of oral administration, the risk of symptoms such as cough possibly caused by FDKP is avoided, and invasion means such as injection are not needed. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition of semaglutide, a preparation method thereof, and an application thereof. Background Art

[0002] As a new generation of hypoglycemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have hypoglycemic effects second only to insulin, and have multiple clinical advantages such as strong hypoglycemic effects, low risk of hypoglycemia, obvious weight loss effects, and cardiovascular benefits. Diabetes is a progressive disease, and GLP-1 receptor agonists, as a transitional therapy between oral hypoglycemic drugs and insulin therapy, have a biological effect of delaying disease progression. From the current clinical application trend, GLP-1 receptor agonists are one of the hypoglycemic drugs with the most market potential globally.

[0003]

[0004] Semaglutide (structure as above), also known as semaplutide, is a glucagon-like peptide-1 (GLP-1) receptor agonist that stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner, thereby reducing blood glucose. In the prior art, semaglutide injection is usually used and administered by subcutaneous injection, which has a long-acting effect and can achieve a dosing frequency of once a week, so as to better exert the drug efficacy. However, subcutaneous injection is an invasive administration method that will cause pain, injection site discomfort and other problems, thus bringing physical and psychological discomfort to patients. At the same time, the injection pen for administration cannot be reused, and the cost of the injection pen accounts for a large part of the R & D, production and use costs of the injection. In addition, there are problems such as complicated filling processes in subcutaneous injection.

[0005] After the somatropin injection (trade name: Ozempic) was launched in 2017 and showed advantages in hypoglycemic, weight loss, cardiovascular system and other aspects, Novo Nordisk A / S overcame the technical limitation that peptide drugs are easily degraded by digestive enzymes and developed an oral preparation of semaglutide tablets (trade name: Rybelsus), which was officially approved by the US Food and Drug Administration (FDA) for listing in September 2019 for blood glucose control in adult patients with T2DM. Sodium N-(8-(2-hydroxybenzoyl)amino)octanoate (SNAC) technology can prevent semaglutide in the stomach from being destroyed and promote cell absorption through the gastric membrane, enabling semaglutide to reach the systemic circulation intact. Although oral semaglutide enhances patient compliance, its bioavailability is far lower than that of subcutaneous injection, only 0.9-1.2%, and the dosing frequency is frequent, requiring once-a-day administration. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the defect that the dosage forms of semaglutide in the prior art are limited, and to provide a pharmaceutical composition of semaglutide, its preparation method and application. The composition of semaglutide of the present invention has one or more of the following effect advantages: higher bioavailability than oral administration, avoiding the risk of symptoms such as cough that may be caused by FDKP (fumaryl diketopiperazine), and not using invasive means such as injection.

[0007] The present invention solves the above technical problems through the following technical solutions:

[0008] The present invention provides a pharmaceutical composition, which comprises an active substance X and a pharmaceutical excipient A. The active substance X is semaglutide or a pharmaceutically acceptable salt thereof; the pharmaceutical excipient A is a diketopiperazine compound shown in Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R a and R a ' are independently selected from 3- to 8-membered cycloalkyl; the 3- to 8-membered cycloalkyl is preferably monocyclic cycloalkyl or bicyclo[n,m,l]alkyl, 2 ≤ n + m ≤ 7; more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -bicyclo[1.1.1]pentyl-, -bicyclo[1.1.2]hexyl-, -bicyclo[1.2.2]heptyl- or bicyclo[2.2.2]octyl, for example

[0011] In one embodiment, the diketopiperazine compound shown in Formula I is

[0012]

[0013] In one embodiment, the pharmaceutically acceptable salt of the diketopiperazine compound shown in Formula I may be an ammonium salt, preferably a diammonium salt; the ammonium ion in the ammonium salt is preferably NH4 + .

[0014] In one embodiment, the mass ratio of the active substance X to the pharmaceutical excipient A is preferably 1:1 to 1:100; more preferably 1:1 to 1:10; for example 1:2, 1:5 or 1:7.

[0015] In one embodiment, the pharmaceutical composition exists in the form of a suspension in a dispersion medium.

[0016] In one embodiment, the pharmaceutical composition exists in a solid form; for example, in the form of a solid dispersion and / or solid particles.

[0017] In one embodiment, when the pharmaceutical composition exists in the form of a suspension in a dispersion medium, the pharmaceutical composition exists in the form of microparticles in the suspension.

[0018] In one embodiment, when the pharmaceutical composition exists in the form of a suspension in a dispersion medium, the dispersion medium of the suspension can be a conventional dispersion medium in the art, preferably water; more preferably distilled water; the mass ratio of the total mass of the active substance X and the pharmaceutical excipient A to the mass of the dispersion medium can be 1% - 20%; preferably 1% - 10%; for example, 3%.

[0019] In one embodiment, when the pharmaceutical composition exists in the form of a suspension in a dispersion medium, the suspension further contains a pH regulator; the pH regulator can be ammonia water; the mass fraction of the ammonia water can be 1% - 40%; for example, 25%. The dosage of the pH regulator is preferably limited to adjusting the pH value of the pharmaceutical excipient A in the dispersion medium in the suspension to 7 - 9; preferably limited to 7.5 - 8.

[0020] In one embodiment, when the pharmaceutical composition exists in the form of solid microparticles; the pharmaceutical excipient A serves as a carrier and self-assembles to form microspheres; the active substance X is uniformly dispersed in the carrier microspheres in a highly dispersed state.

[0021] In one embodiment, when the pharmaceutical composition exists in the form of solid microspheres; the scanning electron microscope of the pharmaceutical composition shows that the blank microspheres are spherical in shape, with a complete morphology, and have multiple pores on the surface. After loading the drug, the surface of the microspheres is relatively smooth, and the active substance is adsorbed and filled into the pores on the surface of the blank microspheres.

[0022] In one embodiment, when the pharmaceutical composition exists in the form of solid microparticles, the particle size of the pharmaceutical composition can be a conventional particle size in the art; preferably, D50 is 2 - 20 μm; more preferably 5 - 10 μm.

[0023] In one embodiment, when the pharmaceutical composition exists in the form of solid microparticles, the X50 of the pharmaceutical composition is 1 - 10 μm; preferably 1 - 4, for example, 3 μm.

[0024] In one embodiment, when the pharmaceutical composition exists in the form of solid microparticles, the fine particle fraction (FPF) of the pharmaceutical composition is 30% - 50%; preferably 40% - 50%; for example, 43.65%.

[0025] In one embodiment, the pharmaceutical composition is composed of the active substance X and the pharmaceutical excipient A.

[0026] In one embodiment, the pharmaceutical composition is composed of the active substance X, the pharmaceutical excipient A, and the dispersion medium.

[0027] In one embodiment, the pharmaceutical composition is composed of the active substance X, the pharmaceutical excipient A, the dispersion medium, and the pH regulator.

[0028] In one embodiment, the pharmaceutical composition is prepared by the following preparation method, and the preparation method includes the following steps: (1) Mix the pharmaceutical excipient A, the dispersion medium, and the pH regulator to obtain suspension 1 containing the pharmaceutical excipient A.

[0029] (2) Sequentially add the dispersion medium and the active substance X to the above suspension 1 to obtain a suspension containing the active substance X and the pharmaceutical excipient A.

[0030] Preferably, it further includes (3) lyophilizing the above suspension to obtain the solid of the pharmaceutical composition.

[0031] In one embodiment, the dispersion medium is a conventional dispersion medium in the art; preferably water; more preferably distilled water.

[0032] In one embodiment, in steps (1) and (2), the mass ratio of the dispersion medium can be (0.1 - 3):1; preferably (0.5 - 2.5):1; for example, 1.5:1.

[0033] In one embodiment, the mass ratio of the total mass of the active substance X and the pharmaceutical excipient A to the mass of the dispersion medium (total mass added twice) is a conventional mass ratio in the art; preferably 1% - 20%; more preferably 1 - 10%; for example, 3%.

[0034] In one embodiment, the pH regulator can be ammonia water.

[0035] In one embodiment, the mass fraction of the ammonia water can be 1% - 40%; for example, 25%.

[0036] In one embodiment, the dosage of the pH regulator may not be specifically limited, as long as the pH value of suspension 1 containing the pharmaceutical excipient A is adjusted to 7 - 9; preferably limited to 7.5 - 8.

[0037] In one embodiment, when the pharmaceutical composition is prepared by the above-mentioned preparation method, the raw materials of the pharmaceutical composition are composed of the substance X, the pharmaceutical excipient A, the dispersion medium, and the pH regulator.

[0038] In one embodiment, the lyophilization is direct (vacuum) lyophilization of the suspension while it is cold, or (for example, at -40 degrees) freezing it into ice cubes and then thawing, and then performing vacuum lyophilization.

[0039] In one embodiment, when the pharmaceutical composition is prepared by the method as described above, the preparation method may further include the following steps: pulverizing the solid of the pharmaceutical composition obtained in step (3) to obtain solid particles containing active substance X and pharmaceutical excipient A.

[0040] In one embodiment, the conditions and operations for pulverization are conventional conditions and operations in the art.

[0041] In one embodiment, the pulverization is carried out under the condition of humidity of 0 - 100%; preferably under the condition of humidity of 30% - 70%.

[0042] In one embodiment, the pulverization is carried out under the condition of pressure of 1 - 10 bar; preferably under the condition of pressure of 2 - 6 bar.

[0043] In one embodiment, the pulverization is preferably carried out by a spiral air classifier mill; for example, pulverized by a spiral air classifier mill of Hosokawa Micron Powder Systems Co., Ltd., model 50AS.

[0044] The present invention also provides a preparation method of the above pharmaceutical composition, which includes the following steps: (1) mixing pharmaceutical excipient A, dispersion medium and pH regulator to obtain suspension 1 containing pharmaceutical excipient A;

[0045] (2) sequentially adding dispersion medium and active substance X to the above suspension 1; obtaining a suspension containing active substance X and pharmaceutical excipient A;

[0046] Preferably, it further includes (3) freeze - drying the above suspension to obtain the solid of the pharmaceutical composition;

[0047] Wherein, the substance X, the pharmaceutical excipient A, the dispersion medium and the pH regulator are all as described above;

[0048] The steps and conditions in the preparation method are all as described above.

[0049] The present invention also provides an inhalation preparation, which contains the pharmaceutical composition of any of the above embodiments.

[0050] The present invention also provides an application of the above pharmaceutical composition or the above inhalation preparation in the preparation of a GLP - 1 receptor agonist or in the preparation of a drug for treating and / or preventing diseases related to the GLP - 1 receptor.

[0051] In one embodiment, the diseases related to the GLP - 1 receptor are diabetes, obesity, cardiovascular diseases or non - alcoholic fatty liver.

[0052] The present invention also provides an application of the above-mentioned pharmaceutical composition or the above-mentioned inhalant preparation in the preparation of a drug; the drug is used for treating and / or preventing diabetes, obesity, cardiovascular diseases or non-alcoholic fatty liver disease.

[0053] The present invention also provides a method for treating and / or preventing a disease related to the GLP-1 receptor, which comprises administering an effective amount of the above-mentioned pharmaceutical composition or inhalant preparation to a patient.

[0054] On the basis of not violating the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0055] The reagents and raw materials used in the present invention are all commercially available.

[0056] The positive and progressive effects of the present invention are as follows: the pharmaceutical composition of the present invention satisfies one or more of the following effect advantages: (1) avoiding preparation invasion; (2) high bioavailability; (3) good physicochemical properties (for example, having a high FPF value and / or lung deposition amount); (4) convenient operation; (5) avoiding side effects such as cough that may be brought by FDKP. Description of the Drawings

[0057] Figure 1 It is the FL scanning electron microscope photograph of Compound 1 (10μm field of view).

[0058] Figure 2 It is the FL scanning electron microscope photograph of Compound 1 (200μm field of view).

[0059] Figure 3 It is the scanning electron microscope photograph of Compound 1-SMG obtained in Step 3 of Example 1.

[0060] Figure 4 It is the photograph of freeze-dried Compound 1-SMG.

[0061] Figure 5 It is the dry powder NGI detection chart of Compound 1-SMG in Example 1.

[0062] Figure 6 It is the dry powder NGI detection chart of Compound S1-SMG.

[0063] Figure 7 It is the dry powder NGI detection chart of Compound S2-SMG.

[0064] Figure 8 It is the dry powder NGI detection chart of Compound S3-SMG.

[0065] Figure 9 It is the dry powder NGI detection chart of Compound S4-SMG. Detailed Embodiments

[0066] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0067] Example 1

[0068] Step 1: Preparation of semaglutide-diketopiperazine suspension:

[0069] 1 g of 3,3'-(((((2S,5S)-3,6-dioxopiperazine-2,5-diyl)bis(butane-4,1-diyl))bis(aza-diyl))bis(carbonyl))bis(bicyclo[1.1.1]pentane-1-carboxylic acid) (Compound 1, the scanning electron microscope spectrum is as Figure 1 and Figure 2 shown) was placed in a 100 mL single-necked flask. At room temperature, 23 mL of distilled water was added, and 25% (mass fraction) ammonia water was added to adjust the pH to 7.5 - 8. Ultrasonic treatment was carried out for 5 minutes, the particles were crushed with a spoon, ultrasonic treatment was continued for 5 minutes, and stirring was carried out for 4 hours. Then 15 mL of distilled water was added, and stirring was carried out for 20 minutes. Next, 143 mg of semaglutide (SMG, with a content of 98%) was added, and stirring was carried out overnight at room temperature.

[0070]

[0071] Step 2: Preparation of semaglutide-diketopiperazine lyophilized powder:

[0072] The above suspension was poured into a 100 mL plastic test tube and freeze-dried by a conventional vacuum freeze dryer to obtain powdery particles. The freeze-dried product was a uniform white solid, and the appearance of the freeze-dried sample was good, without shrinkage and collapse. (As Figure 4 )

[0073] Step 3: Crushing of semaglutide-diketopiperazine lyophilized powder:

[0074] The above dispensed particles were slowly added to a crusher for crushing under a humidity of 30 - 70% and a pressure of 2 - 6 bar to obtain the crushed product (Compound 1 - SMG, the scanning electron microscope spectrum is as Figure 3 )). The crushing particle size was controlled at D50---(5 - 10 μm). After that, it was crushed by a spiral air classifier mill model 50AS from Hosokawa Micron Powder Systems Co., Ltd., and the crushing particle size was controlled at D50---(1 - 10 μm).

[0075] Example 2

[0076] Step 1: Preparation of semaglutide-diketopiperazine suspension

[0077] 2 g of 3,3'-(((((2S,5S)-3,6-dioxopiperazine-2,5-diyl)bis(butane-4,1-diyl))bis(aza-diyl))bis(carbonyl))bis(bicyclo[1.1.1]pentane-1-carboxylic acid) was placed in a 250 mL single-necked flask. At room temperature, 46 mL of distilled water was added, and it was sonicated for 5 minutes. 25% ammonia water was added until the pH was 7.5 - 8, and it was sonicated for 5 minutes. The particles were crushed with a spoon, sonicated for another 5 minutes, stirred for 30 minutes, 30 mL of distilled water was added, stirred for 4 hours, and 286 mg of semaglutide was added, and stirred overnight at room temperature.

[0078] Step 2: Preparation of semaglutide-diketopiperazine lyophilized powder:

[0079] The above suspension was frozen into ice cubes in a -40 °C refrigerator. After thawing, it was poured into two 100 mL plastic test tubes and freeze-dried by a conventional vacuum freeze-dryer to obtain powdery particles. The product after freeze-drying was a uniform white solid, and the appearance of the freeze-dried sample was good, without shrinkage and collapse. (Its morphology is as Figure 4 )

[0080] Step 3: Crushing of semaglutide-diketopiperazine lyophilized powder:

[0081] The above dispensed particles were slowly added to a crusher and crushed under 30 - 70% humidity and 2 - 6 bar pressure to obtain the crushed product (Compound 1-SMG). The crushing particle size was controlled at D50---(5 - 10 μm).

[0082] Example 3

[0083] Step 1: Preparation of semaglutide-diketopiperazine suspension:

[0084] 1 g of 3,3'-(((((2S,5S)-3,6-dioxopiperazine-2,5-diyl)bis(butane-4,1-diyl))bis(aza-diyl))bis(carbonyl))bis(bicyclo[1.1.1]pentane-1-carboxylic acid) (Compound 1, the scanning electron microscope spectrum is as Figure 1 and Figure 2 shown) was placed in a 100 mL single-necked flask. At room temperature, 23 mL of distilled water was added, 25% (mass fraction) ammonia water was added until the pH was 7.5 - 8. It was sonicated for 5 minutes, the particles were crushed with a spoon, sonicated for another 5 minutes, stirred for 4 hours, 15 mL of distilled water was added, stirred for 20 minutes, and 143 mg of semaglutide (SMG, content 98%) was added, and stirred overnight at room temperature.

[0085] Step 2: Preparation of semaglutide-diketopiperazine lyophilized powder:

[0086] The above suspension was poured into a 100 mL plastic test tube and freeze-dried by a conventional vacuum freeze dryer to obtain powdery particles. The product after freeze-drying was a uniform white solid, and the appearance of the freeze-dried sample was good, without shrinkage and collapse. (As Figure 4 )

[0087] Step 3: Crushing of the semaglutide-diketopiperazine lyophilized powder:

[0088] The above sub-packed particles were slowly added to Hosokawa Micron Powder Systems Co., Ltd. under a humidity of 30 - 70% and a pressure of 2 - 6 bar and crushed by a spiral air classifier mill model 50AS to obtain the crushed product (Compound 1-SMG), and the particle size was controlled at D50---(1 - 10 μm).

[0089] Effect Example 1

[0090] SD rats were provided by Shanghai Slake Laboratory Animal Co., Ltd., with the animal production license number: SCXK (Shanghai) 2022.0004; the animal use license number: SCXK (Shanghai) 2019 - 0027.

[0091] Rats of each breed were placed in cages with no more than 5 rats per cage in a constant temperature room at a temperature of 20 - 24 °C, a humidity of 40 - 70%, and a light of 12 h. During the drug metabolism experiment, the animals were fasted for 4 hours and water-deprived for 2 hours during drug administration and blood collection. During the pharmacodynamic experiment, the animals were fasted but not water-deprived.

[0092] The drug administration and blood collection methods for different groups were as follows:

[0093] 1. Compound 1-SMG dry powder aerosol inhalation via the lung administration group

[0094] The specific experimental operation steps are as follows: SD rats were anesthetized with chloral hydrate, and a chloral hydrate solution was intraperitoneally injected at a dose of 3 mL / Kg; after the SD rats were completely anesthetized, they were fixed on the inclined plane of a triangular plate at an angle of 60° to the horizontal plane. The upper teeth of the SD rats were fixed, and the tongue of the SD rats was pulled out with forceps, and the position of the tracheal orifice was observed with an endoscope; an 18G floating needle cannula was inserted into the trachea, and the set dose (6 mg / kg) of Compound 1-SMG dry powder (obtained from Step 3 of Example 1) was loaded at the tail of the cannula, connected to a 5 mL syringe, and the syringe was compressed and purged 3 times, and the dry powder was inhaled into the lungs of the SD rats; after the drug administration, the SD rats were fixed for another 5 min, and then the fixation of the SD rats was released and the SD rats were put back into the cage.

[0095] Blood was collected from the orbital cavity at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 6 h, 9 h, 24 h, 32 h, and 48 h after administration, and the blood was collected into a 1.5 mL EDTA K2 anticoagulant tube. The whole blood was quickly placed in a high-speed centrifuge and centrifuged at 4 °C and 8000 rpm for 10 min. The plasma was aspirated and transferred to a blank centrifuge tube, and stored frozen at -20 °C.

[0096] 2. Inhalation administration group of semaglutide (SMG) aqueous solution via the lung

[0097] Reference compound 1 - Inhalation administration group of SMG dry powder via the lung.

[0098] 3. Intravenous injection group of semaglutide (SMG)

[0099] An appropriate amount of SMG powder was weighed and dissolved in 0.9% physiological saline, diluted to a drug concentration of 0.2 mg / mL, and the drug solution was administered by intravenous injection at 1 mL / Kg.

[0100] Table 1 Main pharmacokinetic parameters of semaglutide in plasma of SD rats after administration of semaglutide

[0101]

[0102]

[0103] AUC(0 - t) refers to the area under the plasma concentration - time curve from time 0 to the last selected time point;

[0104] AUC(0 - inf)_obs represents the area under the curve (AUC) of the observed cumulative distribution function (CDF) in the interval from 0 to positive infinity (0 - inf);

[0105] V_obs represents the version object library;

[0106] CL_obs represents the observation of the drug effect or side effect in the experiment;

[0107] MRT(0 - t) represents the mean residence time from the start of drug administration to time point t;

[0108] MRT(0 - inf)_obs represents the mean residence time of the observation period from the start of administration to infinite time.

[0109] F represents the bioavailability.

[0110] The above - mentioned pharmacokinetic data indicate that the compound 1 - SMG dry powder has good bioavailability (16.02%).

[0111] Effect Example 2

[0112] The Next Generation Pharmaceutical Impactor (NGI) was used to evaluate the fine particle fraction (FPF) of the dry powder. A prepared glycerol solution was dropped onto each layer of the tray to reduce particle bounce and secondary entrainment during the test.

[0113] Preparation method of the glycerol solution: Dissolve 5 g of Tween 80 reagent in 20 mL of ethanol, transfer 1 mL of the solution, and add 5 g of glycerol and shake well to obtain.

[0114] Coating method: Drop two drops on the first tray, and drop one drop on each of the second, third, fourth, fifth, sixth, and seventh trays and coat evenly. Place a glass fiber filter membrane on the multi-orifice cassette (MOC) tray and let it stand for 30 min.

[0115] Connect the throat to the adapter, and connect the inhalation device to the adapter. Turn on the vacuum pump, adjust the flow control valve so that the reading of the flow meter connected to the L-shaped connecting tube is 80 ± 4 L / min. Weigh the drug powder into an anti-static capsule, and place the Breezhaler capsule in the dry powder inhaler (DPI) inhalation device to start the NGI determination.

[0116] Three seconds after the end of the determination, turn off the vacuum pump and repeat the suction three times. Disassemble the device and recover the drugs on each layer and related components with 10 mmol / L phosphate buffer solution. The recovery method is as follows: Dilute the inhalation device and the capsule shell with 25 ml of solvent, dilute the adapter with 25 mL of solvent, dilute the throat with 50 mL of solvent, dilute the first, second, third, fourth, and fifth trays with 25 mL of solvent, dilute the sixth and seventh trays with 10 mL of solvent. After ultrasonically treating the filter membrane of the MOC layer with 10 mL of solvent for 10 min., filter it with a filter, take the continuous filtrate and inject it into the sample vial. Inject the sample for analysis according to the chromatographic conditions, and use Copley inhaler testing data analysis software (CITDAS) version 3.10 for data processing to calculate the FPF of the dry powder inhaler.

[0117] Compound 1-SMG dry powder (prepared in Example 3) was tested by NGI, and the FPF was 43.65%, reaching the ideal deposition site, as Figure 5 shown.

[0118] The following compounds S1 - S4 were prepared with reference to (CN113527216A). The compound S1 - SMG dry powder, compound S2 - SMG dry powder, compound S3 - SMG dry powder, and compound S4 - SMG dry powder were prepared respectively according to the method of Example 3 above. Through NGI detection, their FPF is shown in the following table.

[0119] Table 2

[0120]

[0121]

[0122] Effect Example 3

[0123] The particle sizes of the compound 1 - SMG dry powder (prepared from Example 1), compound S1 - SMG dry powder, compound S2 - SMG dry powder, compound S3 - SMG dry powder, and compound S4 - SMG dry powder were detected (using a laser particle size analyzer of model H4605, HELOS|MYTOS company). Since the physical state of drug particles has a great influence on the performance of dry powder inhalers (DPI), the aerodynamic diameter of dry powder inhaler particles is generally preferably between 1.0 - 5.0 μm. Research shows that aerosolized particle sizes between 1 - 4 μm can be effectively inhaled and deposited in the terminal bronchioles and alveoli of the lungs.

[0124] The inhaled material powder particle size X50 of the compound 1 - SMG dry powder (prepared from Example 3) is about 3 μm, which can be effectively inhaled and deposited in the terminal bronchioles and alveoli of the lungs.

[0125] The compound FDKP - SMG dry powder was prepared according to the method of Example 3 above. The inhaled material powder particle size X50 of the FDKP - SMG dry powder is about 8.8 μm, and the particles are relatively large.

[0126] The inhaled material powder particle size X50 of the compound S1 - SMG dry powder is about 22 μm, and the particles are relatively large.

[0127] The inhaled material powder particle size X50 of the compound S2 - SMG dry powder is about 5.5 μm, and the particles are on the larger side.

[0128] The inhaled material powder particle size X50 of the compound S3 - SMG dry powder is about 7.5 μm, and the particles are large.

[0129] The inhaled material powder particle size X50 of the compound S4 - SMG dry powder is about 5.1 μm, and the particles are relatively large.

Claims

1. A pharmaceutical composition comprising an active substance X and a pharmaceutical excipient A, wherein the active substance X is semaglutide or a pharmaceutically acceptable salt thereof; and the pharmaceutical excipient A is a diketopiperazine compound or a pharmaceutically acceptable salt thereof as shown in formula I: in, R a and R a ' is independently selected from 3-8 membered cycloalkyl.

2. The pharmaceutical composition according to claim 1, characterized in that The R a and R a ', the 3-8 membered cycloalkyl is a monocyclic cycloalkyl or a bicyclo[n,m,l]alkyl, 2≤n+m≤7; preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -bicyclo[1.1.1]pentyl-, -bicyclo[1.1.2]hexyl-, -bicyclo[1.2.2]heptyl- or bicyclo[2.2.2]octyl, more preferably For example 3. The pharmaceutical composition according to claim 2, characterized in that It meets one or more of the following conditions: (1) The diketopiperazine compound as shown in formula I is (2) The pharmaceutically acceptable salt of the diketopiperazine compound as shown in Formula I is an ammonium salt, preferably a diammonium salt; the ammonium ion in the ammonium salt is preferably NH4 + ; (3) The mass ratio of the active substance X to the pharmaceutical excipient A is 1:1-1:100; more preferably 1:1-1:10; for example, 1:2, 1:5 or 1:7; and (4) The pharmaceutical composition exists in the form of a suspension or in a solid form in a dispersion medium; the solid form may be in the form of a solid dispersion and / or solid microparticles.

4. The pharmaceutical composition according to claim 3, characterized in that It meets one or more of the following conditions: (1) When the pharmaceutical composition is in the form of a suspension in a dispersion medium, the pharmaceutical composition is in the form of microparticles in the suspension; (2) When the pharmaceutical composition is in the form of a suspension in a dispersion medium, the dispersion medium of the suspension may be water; preferably distilled water; the mass ratio of the total mass of the active substance X and the pharmaceutical excipient A to the dispersion medium may be 1%-20%; preferably 1%-10%; for example 3%; (3) When the pharmaceutical composition is in the form of a suspension in a dispersion medium, the suspension further comprises a pH adjuster; the pH adjuster may be aqueous ammonia; the mass fraction of aqueous ammonia may be 1%-40%, for example 25%; the amount of the pH adjuster is preferably limited to adjusting the pH value of the pharmaceutical excipient A in the dispersion medium in the suspension to 7-9, preferably 7.5-8; (4) When the pharmaceutical composition is in the form of solid particles, the D50 of the pharmaceutical composition is 2-20 μm; preferably 5-10 μm; and (5) The pharmaceutical composition consists of the active substance X and the pharmaceutical excipient A; or, consists of the active substance X, the pharmaceutical excipient A and the dispersion medium; or, consists of the active substance X, the pharmaceutical excipient A, the dispersion medium and the pH adjuster.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition is prepared by the following preparation method, which comprises the following steps: (1) mixing a pharmaceutical excipient A, a dispersion medium and a pH adjuster to obtain a suspension 1 containing the pharmaceutical excipient A; and (2) adding a dispersion medium and an active substance X to the above suspension 1 in sequence to obtain a suspension containing the active substance X and a pharmaceutical excipient A; Preferably, the method further comprises (3) freeze-drying the suspension to obtain a solid of the pharmaceutical composition; in, The active substance X, the pharmaceutical excipient A, the dispersion medium, the The pH adjuster is as described in any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, characterized in that It meets one or more of the following conditions: (1) In step (1) and step (2), the mass ratio of the two additions of the dispersion medium is (0.1-3):1; preferably (0.5-2.5):1; for example, 1.5:1; (2) The raw materials of the pharmaceutical composition are composed of the substance X, the pharmaceutical excipient A, the dispersion medium and the pH adjuster; (3) The freeze-drying is direct freeze-drying of the suspension, or freezing into ice cubes and then thawing, and then vacuum freeze-drying; the direct freeze-drying is preferably vacuum freeze-drying; the temperature of freezing into ice cubes is -40 degrees; and (4) The preparation method may further comprise the following steps: pulverizing the solid of the pharmaceutical composition obtained in step (3) to obtain solid microparticles containing the active substance X and the pharmaceutical excipient A; the pulverizing may be carried out at a humidity of 0-100%, preferably at a humidity of 30%-70%; the pulverizing may be carried out at a pressure of 1-10 bar, preferably at a pressure of 2-6 bar.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: (1) mixing a pharmaceutical excipient A, a dispersion medium and a pH adjuster to obtain a suspension 1 containing the pharmaceutical excipient A; (2) adding a dispersion medium and an active substance X to the above suspension 1 in sequence to obtain a suspension containing the active substance X and a pharmaceutical excipient A; Preferably, the method further comprises (3) freeze-drying the suspension to obtain a solid of the pharmaceutical composition; Wherein, the definitions of the active substance X, the pharmaceutical excipient A, the dispersion medium, and the pH adjuster are as described in any one of claims 1 to 6; The steps and conditions in the preparation method are as described in claim 5 or 6.

8. An inhalation preparation, characterized in that: It comprises the pharmaceutical composition according to any one of claims 1 to 6.

9. A pharmaceutical composition as claimed in any one of claims 1 to 6 or as claimed in claim 8 The inhalation preparation is used in the preparation of a GLP-1 receptor agonist or a drug for treating and / or preventing a disease associated with the GLP-1 receptor; the disease associated with the GLP-1 receptor is preferably diabetes, obesity, cardiovascular disease or non-alcoholic fatty liver disease.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 or the inhalation preparation according to claim 8 in preparing a medicament; the medicament is used to treat and / or prevent diabetes, obesity, cardiovascular disease or non-alcoholic fatty liver disease.

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