Lily polysaccharide dry powder particle for reducing blood sugar by inhalation administration as well as preparation method and application of lily polysaccharide dry powder particle

Abstract

The invention discloses lily polysaccharide dry powder particles for reducing blood sugar by inhalation administration as well as a preparation method and application of the lily polysaccharide dry powder particles. The lily polysaccharide dry powder is mainly particles which are formed by pelletizing lily polysaccharide and are suitable for inhalation. The preparation method mainly comprises the step of carrying out air jet pulverization or spray freeze drying on the lily polysaccharide to obtain the lily polysaccharide dry powder particles. The lily polysaccharide dry powder particles can be used for inhalation administration of hypoglycemic drugs or drugs for treating diabetes mellitus. Based on an air jet pulverization technology and a spray freeze drying technology, an environment capable of accurately regulating and controlling the particle size and distribution of the lily polysaccharide without the help of other carriers and auxiliary materials is provided, the lily polysaccharide is directly delivered to the lung, gastrointestinal tract damage and the first-pass effect of the liver can be effectively avoided, the administration dosage is reduced, and the onset time is shortened.

Description

Technical Field

[0001] This invention belongs to the field of hypoglycemic agents, specifically relating to a lily polysaccharide dry powder granule for inhalation administration to lower blood sugar, its preparation method, and its application. Background Technology

[0002] Lily, a perennial bulbous plant belonging to the genus *Lilium* in the family Liliaceae, is a valuable economic crop with diverse resources and rich nutrients. It possesses both edible and medicinal value and is one of the first batch of traditional Chinese medicines approved for both food and medicine use. Besides containing starch, protein, and numerous trace elements, lilies also contain various active ingredients such as alkaloids, saponins, and polysaccharides. Lily polysaccharides are a class of high-molecular polymers linked by glycosidic bonds. Studies have shown that polysaccharides, as an important active ingredient in lilies, have multiple effects including immunomodulation, anti-tumor activity, antioxidant activity, and hypoglycemic effects. Numerous studies have demonstrated that lily polysaccharides have excellent hypoglycemic efficacy.

[0003] Diabetes mellitus is one of the fastest-growing global public health emergencies and has been listed by the World Health Organization as one of the four non-communicable diseases requiring close attention. The prevalence of type 2 diabetes is increasing significantly due to sedentary behavior, high-fat diets, and insufficient physical activity. In 2017, 425 million adults worldwide had diabetes, and this number is projected to increase to 629 million by 2045, with China having the highest number of diabetes cases globally. Furthermore, diabetes imposes a heavy economic burden; therefore, it is imperative to explore effective ways to improve the health and quality of life of this population.

[0004] The lungs are a highly vascularized organ in the human body, characterized by a large airway absorption area, high blood flow, strong alveolar epithelial membrane permeability, and low proteolytic enzyme activity. Pulmonary drug delivery systems refer to drug delivery systems that utilize specialized devices to deliver medication directly into the lungs via active or passive inhalation, exerting local or systemic therapeutic effects. Pulmonary drug delivery cleverly combines aerosol technology with the physiological characteristics of the respiratory system, attracting increasing attention in the treatment of systemic diseases and demonstrating significant potential for treating systemic diseases such as diabetes, Parkinson's disease, and schizophrenia. Inhaled pulmonary formulations are highly favored as a novel dosage form due to their rapid absorption, absence of first-pass effect, high bioavailability, and reduced toxicity. Dry powder inhalers, also known as powder aerosols, offer advantages such as high inhalation efficiency, ease of use, absence of propellants, no air pollution, and good stability, making them a hot topic in drug development.

[0005] Polysaccharides from traditional Chinese medicines, as one of the main effective components, have effects such as reducing oxidative stress, inhibiting inflammatory responses, regulating gut microbiota, and improving insulin resistance. The utilization of plant polysaccharides provides a new approach for developing effective hypoglycemic drugs to treat diabetes. Summary of the Invention

[0006] Purpose of the Invention: Addressing the problems existing in the prior art, the purpose of this invention is to provide lily polysaccharide dry powder granules for inhaled administration to lower blood sugar, along with its preparation method and applications. Based on airflow pulverization and spray freeze-drying technologies, this invention provides an environment that allows for precise control of the particle size and distribution of lily polysaccharides without the aid of other carriers and excipients, directly delivering the lily polysaccharides to the lungs. This effectively avoids gastrointestinal damage, reduces the dosage, and shortens the onset time.

[0007] Technical Solution: To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows: In a first aspect, the present invention provides lily polysaccharide dry powder particles, which are mainly dry powder microparticles suitable for inhalation formed by granulation of lily polysaccharide.

[0008] As a specific implementation scheme, the particle size distribution of the lily polysaccharide dry powder particles is: D 10 =0.60-0.76μm, D 50 =2.04-3.74μm, D 90 =4.85-12.97μm.

[0009] As a preferred embodiment, the particle size distribution of the lily polysaccharide dry powder particles is: D 10 =0.60μm, D 50 =2.04μm, D 90 =4.85μm.

[0010] Secondly, the present invention provides a method for preparing the above-mentioned lily polysaccharide dry powder granules, comprising the following two methods: 1. The lily polysaccharide is subjected to air jet milling to obtain the lily polysaccharide dry powder particles.

[0011] This method employs airflow pulverization technology, which uses high-speed compressed air to cause lily polysaccharides to collide and impact with each other, thereby pulverizing them into lily polysaccharide microparticles. This reduces particle size, improves aerodynamic performance such as fine particle fraction, and prepares dry powder microparticles suitable for inhalation.

[0012] The lily polysaccharide particles obtained by air jet milling are immediately collected and sealed in packaging to prevent the lily polysaccharide from absorbing moisture and oxidizing, which would affect the product quality.

[0013] As a specific implementation scheme, the conditions for airflow pulverization are: feed pressure of 3-8 bar and airflow pulverization pressure of 3-8 bar.

[0014] As a preferred embodiment, the conditions for air jet milling are: feed pressure of 8 bar and air jet milling pressure of 8 bar.

[0015] As a specific implementation, the air jet milling is performed using an air jet mill for granulation.

[0016] 2. The lily polysaccharide is spray-frozen-dried to obtain the lily polysaccharide dry powder particles.

[0017] This method employs spray freeze-drying technology, which rapidly freezes materials into solid particles after atomizing them into tiny droplets, and then removes ice crystals through vacuum sublimation, thereby achieving a granulation process. This improves aerodynamic performance such as the fine particle fraction and produces dry powder microparticles suitable for inhalation.

[0018] The lily polysaccharide granules obtained by spray freeze-drying were immediately collected and sealed in packaging to prevent the lily polysaccharides from absorbing moisture and oxidizing, which would affect the product quality.

[0019] As a specific implementation scheme, the conditions for spray freeze drying are: a feed concentration of 1-20 mg / ml, an atomization pressure of 0.1-0.3 MPa, and a feed rate of 15-45 rpm.

[0020] As a preferred embodiment, the conditions for spray freeze drying are: a feed concentration of 8 mg / ml, an atomization pressure of 0.1 MPa, and a feed rate of 30 rpm.

[0021] As a specific implementation, the spray freeze-drying is performed using a spray freeze dryer for granulation.

[0022] Thirdly, the present invention provides the application of the above-mentioned lily polysaccharide dry powder particles in the preparation of drugs for lowering blood sugar or treating diabetes.

[0023] As a specific implementation plan, the drug is an inhalable pulmonary administration preparation.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages: (1) The present invention uses lily polysaccharide powder as raw material. Without using reagents or materials that may be toxic to the human body and have a negative impact on the environment, lily polysaccharide dry powder particles with appropriate size, uniform morphology, good in vitro aerodynamic performance and effective inhalation administration are prepared by airflow pulverization or spray freeze drying.

[0025] (2) This invention improves the current dosage form of lily polysaccharide and provides a method for preparing dry powder inhaler granules. Compared with oral formulations, the prepared lily polysaccharide dry powder granules can avoid gastrointestinal damage. In addition, as the lungs are the hub of immune regulation and metabolic signaling, the inhaler can specifically improve the lung microenvironment of diabetic patients and improve systemic glucose metabolism.

[0026] (3) The preparation method used in this invention has the advantages of simple operation, stable product, high production efficiency, and ease of industrial production. It can effectively reduce the dosage and improve the administration efficiency by inhalation. Attached Figure Description

[0027] Figure 1 This is a particle size distribution diagram of lily polysaccharide dry powder particles prepared based on airflow pulverization technology in Example 1.

[0028] Figure 2 The image shows an automated X-ray diffraction pattern of lily polysaccharide dry powder particles prepared by airflow pulverization technology in Example 1.

[0029] Figure 3 The infrared spectrum analysis of lily polysaccharide dry powder particles prepared by airflow pulverization technology in Example 1 is shown.

[0030] Figure 4 This is a scanning electron microscope image of lily polysaccharide dry powder particles prepared by airflow pulverization technology in Example 1.

[0031] Figure 5 This is a scanning electron microscope image of lily polysaccharide dry powder particles prepared based on spray freeze-drying technology in Example 4.

[0032] Figure 6 The mass ratio diagram of the lily polysaccharide dry powder particles prepared in Examples 1 and 4 deposited in each stage collector of the Next Generation Pharmaceutical Impactor (NGI). Detailed Implementation

[0033] The technical solution of the present invention will be described in detail below through specific embodiments, but the scope of protection of the present invention is not limited to the embodiments described.

[0034] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples are commercially available products.

[0036] The present invention relates to the characterization and evaluation of lily polysaccharide dry powder particles prepared by air jet milling and spray freeze drying. The characterization and evaluation methods are as follows: I. Particle size: The dry powder particles were characterized using a laser particle size analyzer; II. Crystalline state: Crystallinity was determined using an automated X-ray diffractometer; III. Chemical Properties: Fourier transform infrared spectroscopy was used to analyze the molecular structure and chemical bonds of the dry powder particles; IV. Morphological and Appearance Characteristics: The microscopic morphology of the dry powder particles was recorded by scanning electron microscopy. V. Aerodynamic characteristics: Ten capsules containing dry powder particles were separated using a new generation pharmaceutical disc impactor (NGI) with an airflow rate of 60 L / min. The number of particles deposited at each stage was determined by gravimetric analysis.

[0037] Example 1

[0038] The preparation method of lily polysaccharide dry powder granules includes the following steps: (1) Pulverization of lily polysaccharide raw material: Weigh a certain mass of lily polysaccharide, use an air jet mill, and under the conditions of a feed pressure and an air jet milling pressure of 8-8 bar, pulverize the lily polysaccharide by high-speed compressed air to obtain lily polysaccharide microparticles, reduce particle size, and improve aerodynamic performance such as fine particle fraction. (2) Collection and storage: Pack and seal the qualified dry granules obtained in step (1), and store the finished product in a cool, dry place at low temperature.

[0039] Example 2

[0040] The preparation method of lily polysaccharide dry powder granules includes the following steps: (1) Pulverization of lily polysaccharide raw material: Weigh a certain mass of lily polysaccharide, use an air jet mill, and under the conditions of a feed pressure and an air jet milling pressure of 6-6 bar, pulverize the lily polysaccharide by high-speed compressed air to obtain lily polysaccharide microparticles, reduce particle size, and improve aerodynamic performance such as fine particle fraction. (2) Collection and storage: Pack and seal the qualified dry granules obtained in step (1), and store the finished product in a cool, dry place at low temperature.

[0041] Example 3

[0042] The preparation method of lily polysaccharide dry powder granules includes the following steps: (1) Pulverization of lily polysaccharide raw material: Weigh a certain mass of lily polysaccharide, use an air jet mill, and under the conditions of a feed pressure and an air jet milling pressure of 3-3 bar, pulverize the lily polysaccharide by high-speed compressed air to obtain lily polysaccharide microparticles, reduce particle size, and improve aerodynamic performance such as fine particle fraction. (2) Collection and storage: Pack and seal the qualified dry granules obtained in step (1), and store the finished product in a cool, dry place at low temperature.

[0043] Example 4

[0044] The preparation method of lily polysaccharide dry powder granules includes the following steps: (1) Dissolving lily polysaccharide raw material: Weigh a certain mass of lily polysaccharide and dissolve it in pure water to obtain a raw material solution concentration of 8 mg / ml; (2) Spray freezing: Add an appropriate amount of liquid nitrogen to the collection tray of the spray freezer, and use a silicone hose with an inner diameter of 2 mm to transport the solution obtained in step (1). Set the spray freezer to atomize the lily polysaccharide solution at an atomization pressure of 0.1 MPa and a feed rate of 30 rpm, and atomize the solution evenly into the liquid nitrogen in the collection tray. Transfer the collected sample to a beaker. (3) Freeze-drying: Transfer the sample collected in step (2) into a beaker, wait for the liquid nitrogen to evaporate, cover the mouth of the beaker with tin foil with holes punched in the surface, put it into a freeze dryer for freeze-drying, and obtain lily polysaccharide microparticles after freeze-drying. (4) Collection and storage: Pack and seal the qualified dry granules obtained in step (3), and store the finished product in a cool, dry place at low temperature.

[0045] Example 5

[0046] Physicochemical characterization of lily polysaccharide dry powder granules (1) The dry powder granule product obtained in Example 1 was analyzed under a laser particle size analyzer to obtain D 50 The particle size was 2.04 μm. The dry powder granules obtained in Example 4 were analyzed using a laser particle size analyzer, yielding a D0.04. 50 The particle size distribution was 3.44 μm. Detailed results of the particle size distribution before and after pulverization in Examples 1-3 are shown in Table 1 below.

[0047] Table 1. Particle size of lily polysaccharides before and after air jet milling

[0048] (2) The dry powder granule product obtained in Example 1 was analyzed under an X-ray diffraction analyzer. The XRD pattern of the obtained dry powder granule product is shown in the figure. Figure 2 .

[0049] (3) The dry powder granule product obtained in Example 1 was analyzed under a Fourier transform infrared spectrometer. The FTIR chromatogram of the obtained dry powder granule product is shown in the figure. Figure 3 .

[0050] (4) The dry powder granule product obtained in Example 1 was subjected to SEM imaging under a scanning electron microscope. The SEM image of the obtained dry powder granule product is shown in the figure below. Figure 4 .

[0051] (4) The dry powder granule product obtained in Example 4 was subjected to SEM imaging under a scanning electron microscope. The SEM image of the obtained dry powder granule product is shown in the figure below. Figure 5 .

[0052] Example 6

[0053] Aerodynamic performance evaluation of lily polysaccharide dry powder granules Ten capsules containing dry powder from Example 1 or Example 4 were separated using a new generation pharmaceutical disc impactor (NGI) with an air flow rate of 60 L / min. The amount of particles deposited at each stage was determined by gravimetric analysis.

[0054] The mass ratio of the obtained dry powder granules in each stage of the NGI collector is shown in the figure. Figure 6 Most of the particles were deposited in the 2nd to 5th layers, which is consistent with the particle size detection results and meets the inhalation size.

[0055] Example 7

[0056] Experiment: Animal functional experiment on the hypoglycemic effect of lily polysaccharide dry powder granules 1. Materials and Methods 1.1 Sample: The sample prepared in Example 1 1.2 Animals: Male SPF-grade SD rats (6 weeks old, 180±20 g) were purchased from Nanjing Zhonghua Biotechnology Co., Ltd.

[0057] 1.3 Instruments and reagents: High-fat feed was purchased from Beijing Boaigang Biotechnology Co., Ltd.; streptozotocin was purchased from Shanghai McLean Biochemical Technology Co., Ltd.; Roche® Gold Glucose Meter was purchased from Roche.

[0058] 1.4 Experimental Methods: Twenty 6-week-old SPF-grade SD rats were selected and acclimatized for one week with free access to food and water. Five rats were randomly selected as the blank control group and fed a basal diet, while the remaining 15 rats were used as the experimental group and fed a high-fat diet. Four weeks later, the experimental group rats were intraperitoneally injected with fresh STZ buffer (30 mg / kg) for three consecutive days, while the blank control group rats were injected with citrate-sodium citrate buffer. One week later, fasting blood glucose was measured. A fasting blood glucose level greater than 16.7 mmol / L, accompanied by polydipsia, polyphagia, and polyuria, was considered a successful model. The rats were then randomly divided into a model group, an oral administration group (500 mg / kg / d), and an inhalation group (500 mg / kg / d), with five rats in each group. Throughout the animal experiment, the healthy rats in the blank control group were fed a basal diet, while the model group, oral administration group, and inhalation group were fed a high-fat diet. After four weeks of continuous administration, the rats were fasted for 12 hours, and their fasting blood glucose levels were measured to observe the effect of the test substance on the fasting blood glucose of normal animals.

[0059] 2. Results The effects of lily polysaccharide powder granules on fasting blood glucose in hyperglycemic rats are shown in Table 2 below.

[0060] Table 2. Effects of the lily polysaccharide powder granules of the present invention on fasting blood glucose in hyperglycemic rats.

[0061] 3. Summary The results of this experiment show that the granules of this invention have no effect on fasting blood glucose in normal rats. Lily polysaccharides exhibit a hypoglycemic effect at a dose of 500 mg / kg / day, with the inhalation group showing significantly better results than the oral group. The lily polysaccharide dry powder granules of this invention, administered via inhalation, directly act on the lungs—a key hub for immune regulation and metabolic signaling—and can specifically improve the homeostasis of the lung microenvironment in diabetic patients. It can precisely regulate the structure of the lung flora, enrich the abundance of beneficial bacteria in the lungs, inhibit the excessive proliferation of harmful bacteria, and enhance the lung's immune regulation function and metabolic signal transduction efficiency by optimizing the lung flora balance. Furthermore, by leveraging the close connection between the lungs and the systemic metabolic network, it improves the state of systemic glucose metabolism disorder from the source, achieving a hypoglycemic effect while providing an innovative treatment pathway for diabetic patients that balances local microenvironment optimization and systemic metabolic regulation.

[0062] The embodiments of the present invention have been described in detail above with reference to specific examples. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A lily polysaccharide dry powder particle, characterized in that, The lily polysaccharide dry powder particles are mainly formed by granulating lily polysaccharide to form dry powder particles suitable for inhalation.

2. The lily polysaccharide dry powder particles of claim 1, wherein, The particle size distribution of the lily polysaccharide dry powder particles is: D 10 = 0.60-0.76 μm, D 50 = 2.04-3.74 μm, D 90 = 4.85-12.97 μm.

3. The lily polysaccharide dry powder particles of claim 1, wherein, The particle size distribution of the lily polysaccharide dry powder particles is: D 10 = 0.60 μm, D 50 = 2.04 μm, D 90 = 4.85 μm.

4. The preparation method of lily polysaccharide dry powder particles according to any one of claims 1-3, characterized in that, The method comprises the following steps: The lily polysaccharide is subjected to jet milling or spray freeze drying to obtain the lily polysaccharide dry powder particles.

5. The preparation method of lily polysaccharide dry powder particles according to claim 4, characterized in that, The jet milling is performed under the following conditions: the feeding pressure is 3-8 bar, and the jet milling pressure is 3-8 bar; preferably, the feeding pressure is 8 bar, and the jet milling pressure is 8 bar.

6. The preparation method of lily polysaccharide dry powder particles according to claim 4, characterized in that, The spray freeze drying is performed under the following conditions: the concentration of the drug solution is 1-20 mg / ml, the atomization pressure is 0.1-0.3 MPa, and the feeding rate is 15-45 rpm; preferably, the concentration of the drug solution is 8 mg / ml, the atomization pressure is 0.1 MPa, and the feeding rate is 30 rpm.

7. The preparation method of lily polysaccharide dry powder particles according to claim 4, characterized in that, The jet milling is performed by using a jet mill, and the spray freeze drying is performed by using a spray freeze dryer.

8. Use of the lily polysaccharide dry powder particles according to any one of claims 1-3 in the preparation of a medicament for lowering blood sugar or treating diabetes.

9. Use according to claim 8, characterized in that, The medicament is an inhalable pulmonary administration preparation.

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