Kalii dehydrographolidi succinas lung inhalation powder inhalation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to kalii dehydrographolidi succinas lung inhalation dry powder as well as a preparation method and application thereof. The dry powder inhalation comprises an active component and an excipient, the active component is potassium dehydroandrographolide succinate, and the excipient comprises a filling agent, an atomization reinforcing agent and an antistatic agent; the filling agent comprises alpha-lactose monohydrate, trehalose, glucose, mannitol or xylitol; the atomization enhancer comprises leucine, alanine or glycine; the antistatic agent is poloxamer; the dry powder inhalation comprises the following components in percentage by mass volume w / v: 0.5%-1.4% of potassium dehydroandrographolide succinate, 0%-0.45% of alpha-lactose monohydrate, 0.45%-1.55% of leucine, 0.02%-0.4% of poloxamer 188 and 1%-5% of total solid content. The kalii dehydrographolidi succinas pulmonary inhalation dry powder inhalation with good dispersibility and in-vitro deposition performance is prepared; direct lung local drug delivery is achieved, the drug dosage is reduced, and the lung local drug concentration is increased.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a chuanhuning pulmonary inhalation powder aerosol and a preparation method and application thereof. Background Art

[0002] Potassium dehydroandrographolide succinate (PDS) is the full name of dehydroandrographolide succinate monopotassium salt, and its chemical name is 14-dehydroxy-11,12-didehydroandrographolide-3,19-disuccinate monopotassium salt. PDS has the effects of antipyretic and anti-inflammatory, promoting adrenal cortex function and sedation; it can also promote the phagocytic ability of neutrophils and macrophages; it can also inhibit inosine-5-phosphate dehydrogenase, block the conversion of inosine to guanylate, and thus inhibit the synthesis of viral RNA and DNA; PDS has an inactivating effect on adenovirus type 3, influenza virus type A1, type A3, and respiratory syncytial virus, and has a certain effect on respiratory diseases. In China, the existing PDS injection is mainly used for the treatment of viral pneumonia and upper respiratory tract infections, and is an antiviral drug. In clinical applications, injection of PDS has been reported to cause many adverse reactions in the human body, such as allergies and liver damage. Adverse reactions may be related to impurities produced by the degradation of drug solutions and excessive dosage of injections. In addition, injections are invasive, with poor patient compliance and inconvenient use. To improve the existing defects of PDS injections, it is considered to prepare PDS into powder aerosols. Compared with oral administration, pulmonary administration is not affected by food and first-pass metabolism, and reduces the effective dose, thereby reducing related side effects. Compared with injections, pulmonary administration can reduce the dosage and avoid pain, making it easier for patients to use. Compared with other dosage forms for the treatment of lung diseases, pulmonary administration has obvious advantages. Summary of the invention

[0003] In view of the above situation, in order to overcome the shortcomings of existing dosage forms, the purpose of the present invention is to provide a Chuanhuning powder inhaler for pulmonary inhalation and a preparation method; the prepared powder inhaler has good dispersibility and in vitro deposition performance, and can be used to solve the problems of large dosage, many adverse reactions, and poor patient compliance of Chuanhuning injection.

[0004] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0005] The invention provides a chuanhuning pulmonary inhalation powder for treating viral pneumonia, which comprises an active ingredient and an excipient, wherein the active ingredient is chuanhuning, and the excipient comprises a filler, an atomization enhancer and an antistatic agent; the filler comprises α-lactose monohydrate, trehalose, glucose, mannitol or xylitol; the atomization enhancer comprises leucine, alanine or glycine; and the antistatic agent is a poloxamer.

[0006] In the above technical solution, further, the powder inhaler comprises, by mass volume w / v percentage: 0.5% to 1.4% of succinate, 0% to 0.45% of α-lactose monohydrate, 0.45% to 1.55% of leucine, 0.02% to 0.4% of poloxamer 188, and a total solid content of 1% to 5%.

[0007] In the above technical solution, further, the powder inhaler comprises, by mass volume w / v percentage content: 0.5% to 1% of succinate, 0.1% to 0.3% of α-lactose monohydrate, 0.45% to 1.0% of leucine, 0.02% to 0.04% of poloxamer 188, and a total solid content of 1 to 3%.

[0008] In the above technical solution, further, the powder inhaler is calculated by mass volume w / v percentage content: 0.5% of chuanshuning, 0.1295% of α-lactose monohydrate, 0.4745% of leucine, and 0.0200% of poloxamer; the total solid content is 1.124%. In the above technical solution, further, the preparation method of the aforementioned chuanshuning pulmonary inhalation powder inhaler for treating viral pneumonia includes: mixing and dissolving the active ingredient and the excipient raw materials in water, adjusting the pH to 5.0-7.0, and spray drying; the inlet temperature of the spray drying is 110-160°C, the feed rate is 4.5-9.0mL / min, the pumping rate is 70-95%, and the gas flow rate is 586.25-921.25L / h.

[0009] In the above technical solution, further, the inlet temperature of the spray drying is 120° C., the feed rate is 4.5 mL / min, the pumping rate is 95%, and the gas flow rate is 753.75 L / h.

[0010] The present invention also provides the use of the above-mentioned Chuanhuning pulmonary inhalation powder in preparing a medicine for treating viral pneumonia.

[0011] The powder inhaler of the present invention can be packaged in gelatin or carboxymethyl cellulose (HPMC) capsules when used, and administered through a dry powder inhalation device.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention combines Chuanhuning with excipients and spray drying to prepare Chuanhuning powder inhalation for pulmonary inhalation. The prepared dry powder can be quickly blown out and atomized, suitable for inhalation into the deep lung, increasing the lung concentration of the drug and prolonging the drug's lung residence time. In terms of preparing powder inhalation, spray drying has obvious advantages. Compared with air flow crushing and ball milling, the particle size obtained by spray drying has a better aerodynamic diameter, and it has the "one-step method" feature of converting from liquid to powder; compared with spray freeze drying, it has a lower application cost, a more convenient process, and is more conducive to industrialization. Compared with existing dosage forms, the powder inhalation prepared by the present invention is more suitable for active use by patients. Compared with intravenous administration, pulmonary administration reduces the dosage, increases drug lung exposure, improves patient compliance, and is also convenient for storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The aerodynamic diameter and in vitro deposition rate of the powder inhaler prepared by using different drug concentrations in Example 2;

[0015] Figure 2 The aerodynamic diameter and in vitro deposition rate of the powder inhaler prepared by using different concentrations of α-lactose monohydrate in Example 3;

[0016] Figure 3 The aerodynamic diameter and in vitro deposition rate of the chuanhuning powder inhaler prepared by using different concentrations of leucine in Example 4;

[0017] Figure 4 In Example 5, the aerodynamic diameter and in vitro deposition rate of the Chuanhuning powder inhaler were obtained by using different concentrations of p188;

[0018] Figure 5 Various index diagrams of the Chuanhuning powder inhaler prepared with different solid contents in Example 7; A. D10, D50, D90, Span; B. in vitro deposition rate and aerodynamic diameter;

[0019] Figure 6 Various index diagrams of the Chuanhuning powder inhaler prepared at different inlet temperatures in Example 8; A. D10, D50, D90, Span; B. in vitro deposition rate and aerodynamic diameter;

[0020] Figure 7 Various index diagrams of the Chuanhuning powder inhaler prepared at different feed rates in Example 9; A. D10, D50, D90, Span; B. in vitro deposition rate and aerodynamic diameter;

[0021] Figure 8 Various index diagrams of the Chuanhuning powder inhaler prepared by different pumping rates in Example 10; A. D10, D50, D90, Span; B. in vitro deposition rate and aerodynamic diameter;

[0022] Fig. 9 Various index diagrams of the Chuanhuning powder inhaler prepared by different gas flow rates in Example 11;

[0023] A.D10, D50, D90, Span; B. In vitro deposition rate and aerodynamic diameter;

[0024] Fig.10 SEM images of the powder in Example 12; A. PDS API; B. PDS after spray drying; C. Excipients after spray drying; D. PDS powder aerosol;

[0025] Fig.11 The weight loss graph of the Chuanhuning powder inhaler measured by TGA in Example 12;

[0026] Fig.12 X-ray powder diffraction pattern in Example 12; A. Chuanhuning API; B. Chuanhuning after spray drying; C. α-lactose monohydrate; D. P188; E. Leucine; F. Excipients after spray drying; G. Chuanhuning powder inhaler; H. Physical mixture;

[0027] Fig.13 Infrared spectrum absorption diagram of the powder in Example 12; A. PDS raw material; B. PDS after spray drying; C. α-lactose monohydrate before spray drying; D. P188 before spray drying; E. Leucine before spray drying; F. excipients after spray drying; G. PDS powder aerosol; H. physical mixture of raw materials and excipients;

[0028] Fig.14 The atomization state of the Chuanhuning powder inhaler in Example 12;

[0029] Fig.15 Pairwise comparison of the drug-time curves of various tissues under different administration methods in Example 13; A. plasma; B. heart; C. liver; D. spleen; E. lung; F. kidney; G. trachea;

[0030] Fig.16 Drug distribution diagrams in different tissues after tail vein injection or pulmonary administration in Example 13; A. tail vein injection; B. pulmonary administration. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

[0032] Example 1

[0033] The mixture of PDS, lactose, leucine and p188 was dissolved in water, and NaOH was added to adjust the pH to 6.0, and the mixture was stirred until dissolved, and then spray-dried. The inlet temperature of the spray-drying process was 120°C, the feed rate was 4.5 mL / min, the pumping rate was 95%, and the gas flow rate was 753.75 L / h. The solid contents of PDS, lactose, leucine and p188 were 1%, w / v, 0.259%, w / v, 0.949%, w / v, and 0.040%, w / v, respectively.

[0034] Example 2

[0035] According to the preparation method of Example 1, the PDS content was changed to select 0.6%, 0.8%, 1.0%, 1.2%, and 1.4% of the drug content respectively. Figure 1 As can be seen from Table 1, as the drug content decreases, the proportion of excipients increases, and D[4,3] is less affected by drug concentration. The Da values ​​are all large and some exceed 5μm, which is not conducive to the inhalation of DPI. The reduction in drug content leads to a decrease in compression, but the effect on tap density is not very obvious. In addition, a lower drug content increases the RF value of DPI, and the addition of excipients is beneficial to DPI.

[0036] Table 1 Effects of different drug concentrations on the performance of Chuanhuning powder inhaler

[0037]

[0038] Example 3

[0039] According to the preparation method of Example 1, the content of α-lactose monohydrate was changed to 0%, 0.05%, 0.15%, 0.25%, and 0.45% of α-lactose monohydrate. Figure 2 As can be seen from Table 2, with the increase of α-lactose monohydrate content, D[4,3] and Da values ​​both showed a trend of first decreasing and then increasing. The increase of α-lactose monohydrate content also affected the compressibility and in vitro deposition rate of the powder aerosol. In the range of 0% to 0.45%, the compressibility gradually decreased, and the RF value first increased and then decreased.

[0040] Table 2 Effect of α-lactose monohydrate concentration on Chuanhuning powder inhaler

[0041]

[0042] Example 4

[0043] According to the preparation method of Example 1, the leucine content was changed to 0.55%, 0.75%, 0.95%, 1.15%, 1.35%, and 1.55% leucine content respectively. Figure 3As can be seen from Table 3, with the increase of leucine content, D[4,3] increases, and the Da value basically exceeds 5μm. The tap density decreases relatively with the increase of leucine content, which may be due to the shelling of leucine, which leads to the decrease of tap density. From 0.55% to 1.55%, RF first increases and then decreases.

[0044] Table 3 Effect of leucine concentration on chuanhuning powder inhaler

[0045]

[0046]

[0047] Example 5

[0048] According to the preparation method of Example 1, the P188 content was changed to 0.04%, 0.10%, 0.20%, and 0.40% P188 content respectively. Figure 4 It can be seen from Table 4 that with the increase of P188 content, the tap density decreases significantly and the compression increases. From 0.04% to 0.40%, RF increases first and then decreases.

[0049] Table 4 Effect of P188 concentration on Chuanhuning powder aerosol

[0050]

[0051] Example 6

[0052] The Box-Benhnken response surface method (BBD) was used to design a three-factor three-level experiment. Yield, aerodynamic diameter, compression, and in vitro deposition rate (RF) were used as evaluation indicators. The concentration of PDS was fixed at 1% and the concentrations of α-lactose monohydrate, leucine, and P188 were optimized.

[0053] Table 5 Different factors and levels in the BBD experiment

[0054]

[0055] The experimental design was performed by Design-expert software, and the optimal theoretical value was automatically calculated by Design expert 11 software. The spray drying was performed according to the optimal prescription obtained by BBD response surface experiment optimization, and the actual yield, Da, CI, and RF of the obtained Chuanhuning powder aerosol were within 5% of the relative error of the theoretical values ​​given by the software.

[0056] Table 6 Optimal prescription values ​​obtained through BBD experiment

[0057]

[0058]

[0059] Example 7

[0060] According to the preparation method of Example 1, the total solid content was selected to be 1.124%, 2.248%, 4.496%, and 8.992%, respectively. Figure 5 As can be seen from Table 7, with the increase of total solid content, the particle size of the spray-dried powder increases. With the increase of total solid content, the tap density changes less and the compression increases. When the total solid content is 1.124%, the excipients and APIs are well dissolved, the Da value of the obtained powder is in the range of 1μm to 5μm, and the RF value and yield are the largest. When the total solid content is 8.992%, the amount of excipients and APIs added has exceeded the maximum solubility; during spray drying, the suspension clogs the nozzle.

[0061] Table 7 Effect of total solid content on Chuanhuning powder aerosol

[0062]

[0063] Example 8

[0064] According to the preparation method of Example 1, the inlet temperatures were selected to be 110°C, 120°C, 140°C, and 160°C, respectively. Figure 6 As can be seen from Table 8, from 110°C to 160°C, the powder yield is above 80%, and the Da value is within the qualified range. At 110°C, the powder yield is lower than that at the other three temperatures, which may be related to its higher water content. Although the powder obtained at 160°C has the lowest water content, its RF value is low, and its corresponding outlet temperature is above 70°C, which will cause certain damage to powders with low glass transition temperature or low melting point. Although the water content of the powder obtained at 120°C is not the lowest, the RF value of the powder is higher and the aerodynamic particle size is also suitable for inhalation.

[0065] Table 8 Effect of inlet temperature on Chuanhuning powder aerosol

[0066]

[0067] Example 9

[0068] According to the preparation method of Example 1, the feed rates were 4.5 mL / min, 6.0 mL / min, 7.5 mL / min, and 9.0 mL / min, respectively. Figure 7As can be seen from Table 9, when the feed rate is 4.5mL / min and 6.0mL / min, the yield of the powder is high, and when the feed rate is 7.5mL / min and 9.0mL / min, the water content is high and the yield is relatively low. When the feed rate is set to 9.0mL / min, it is observed that many small water droplets remain in the cyclone separator of the spray dryer. With the increase of the feed rate, the Da of the powder is within the appropriate range, and the particle size increases significantly.

[0069] Table 9 Effect of feed rate on Chuanhuning powder aerosol

[0070]

[0071] Example 10

[0072] According to the preparation method of Example 1, the pumping rates are selected to be 70%, 80%, and 95% respectively; Figure 8 It can be seen from Table 10 that with the decrease of the pumping rate, the particle size of the particles gradually decreases. The water content and RF corresponding to the 95% pumping rate are both good. In summary, the 95% pumping rate is finally selected as the optimal condition.

[0073] Table 10 Effect of suction rate on Chuanhuning powder inhaler

[0074]

[0075] Embodiment 11

[0076] According to the preparation method of Example 1, the gas flow rates were 586.25 L / h, 753.75 L / h, and 921.25 L / h, respectively. Fig. 9 It can be seen from Table 11 that with the increase of gas flow rate, the particle size of the powder gradually decreases. When the gas flow rate is 753.75 L / h, the tap density and compression are small, and the RF value of the powder is the largest.

[0077] Table 11 Effect of gas flow rate on Chuanhuning powder aerosol

[0078]

[0079] Example 12

[0080] PDS, lactose, leucine and p188 are mixed and dissolved in water, NaOH is added to adjust the pH to 6.0, and the mixture is spray-dried; the inlet temperature of the spray-drying is 120°C, the feed rate is 4.5 mL / min, the pumping rate is 95%, and the gas flow rate is 753.75 L / h; the solid contents of PDS, lactose, leucine and p188 are 0.5000%, w / v, 0.1295%, w / v, 0.4745%, w / v, and 0.0200%, w / v, respectively, and the total solid content is 1.124%, w / v.

[0081] (1) Yield: It is the ratio of the powder collected by spray drying to the input material; the yield of this embodiment is as high as 91.6%.

[0082] (2) Powder morphology: Observe the particle morphology and surface characteristics using a scanning electron microscope (SEM). Take a small amount of powder and fix it evenly on a conductive tape, then place the sample on the SEM for observation and image collection. Fig.10 It can be seen from the SEM image that the powder of the PDS raw material has an elongated flake structure. When the PDS solution is spray-dried, the spray-dried powder particles are spherical with a smooth surface; Figure B shows particles of different sizes, large particles are more dispersed, and small particles are aggregated; therefore, the spray-dried PDS powder is easy to aggregate and has poor atomization performance. In Figure C, the particles formed by spray drying of the blank excipient solution (α-lactose monohydrate, leucine, P188) have a porous and wrinkled structure, and small particles can enter the pores, thereby reducing the aggregation of small particles. Figure D shows that the particles of the final preparation are almost wrinkled, and some small particles are wrapped in the concave particles. Compared with the spray-dried PDS powder, the particles of the final preparation have better dispersibility and are more conducive to being inhaled into the lungs. This also shows that the added excipients have a certain effect on PDS and improve the performance of the spray-dried powder.

[0083] (3) Particle size: D10, D50, D90, D[4,3] are 0.63±0.01μm, 2.27±0.02μm, 4.93±0.02μm, 2.66±0.12μm, and Da is 1.88±0.08μm; span is 1.89±0.03. It can be judged from the particle size of the powder that PDS-DPI meets the requirements of pulmonary inhalation and can be inhaled into the deep lung.

[0084] (4) Moisture content: A lower moisture content is conducive to the storage and atomization of DPI, while a higher moisture content will cause powder agglomeration, which is not conducive to powder atomization. Fig.11 The weight loss graph of PDS-DPI shows that the decrease in powder mass is related to its water content. The optimal water content of PDS-DPI measured by TGA is 2.228%.

[0085] (5) Flowability: The tap density of the obtained dry powder is 0.50±0.02g / cm 3 , the compression degree is 45.10±0.17%.

[0086] (6) X-ray powder diffraction analysis (X-RPD): In the powder X-RPD diagram ( Fig.12 ), A shows that Chuanhuning, α-lactose monohydrate, P188, and leucine before spray drying all have obvious diffraction peaks, indicating that they are in a crystalline state. B shows that the diffraction peak of the PDS powder after spray drying disappears significantly; after spray drying, Chuanhuning turns into an amorphous state. F shows that the crystalline diffraction peak of leucine in the spray drying excipient basically exists, however, the crystalline diffraction peak of α-lactose monohydrate is damaged a lot, and part of it exists in an amorphous state. G shows that in the Chuanhuning powder aerosol, the diffraction peak of leucine is obviously present, and other substances have basically turned into amorphous states. It is speculated that the PDS powder may be wrapped in the shell formed by leucine.

[0087] (7) FTIR analysis: Fig.13 It can be seen that 1750cm in A -1 The two absorption peaks on the left and right represent the characteristic peaks of vc=o of saturated esters and unsaturated esters in the PDS structure; 3000cm -1 The peaks on the left and right include the peaks of carbon-hydrogen stretching vibration vC-H and carboxylic acid vOH. B represents the PDS powder after spray drying; after X-RPD and DSC characterization, it is amorphous; A represents the PDS raw material, which is in a crystalline state; different crystalline forms may cause the 1625cm -1 The absorption peak here is inconsistent with that in A. In C, 3250cm -1 The broad absorption peak at 1500-1250 cm-1 may be the hydroxyl stretching vibration peak vOH of α-lactose monohydrate; -1 The absorption peak between 3000cm and 3000cm may be the carbon oxygen single bond stretching vibration peak (vOH) or the hydroxyl in-plane bending vibration peak (βOH). -1 The absorption peak at 1125 cm is attributed to the stretching vibration of hydroxyl group (vOH); -1 The broad peak near 3000 cm-1 may be caused by ether stretching vibration (vC-OC). -1 The absorption peak near the OH stretching vibration peak (vOH) is broad and blunt, which is due to the OH stretching vibration peak (1625cm -1 The nearby peaks are related to the bending vibration of the primary amine (δNH). A comprehensive comparison of Figures F, G, and H shows that no other absorption peaks appear, indicating that there is no bonding between excipients and excipients, or between excipients and drugs.

[0088] (8) Inhalation performance: Observe with the naked eye. Fig.14As shown, the dry powder can be blown out and atomized quickly. There is 30 mg of powder in a HPMC capsule shell. As can be seen from Table 12, the discharge fraction is 95.55±1.41%, and only a small amount of powder remains in the drug delivery device. The PDS-DPI has good atomization performance. 28.66±0.42 mg was discharged from the capsule shell, and the amount of powder discharged accounted for 95.55±1.41% of the amount loaded into the capsule, which met the requirements of the pharmacopoeia. Through the double-stage impactor, the deposition rates of PDS-DPI in the capsule shell, impactor throat, primary stage, and secondary stage were measured to be 2.56±0.55%, 1.31±0.28%, 10.84±0.87%, and 77.62±3.63%, respectively; the results showed that the amount of drug deposited in the bottle of the secondary stage was the largest, indicating that PDS-DPI is suitable for inhalation into the deep lung.

[0089] Table 12 Various indicators of in vitro deposition of Chuanhuning powder aerosol

[0090]

[0091] Example 13 Study on tissue distribution of Chuanhuning powder inhalation after pulmonary inhalation and Chuanhuning injection

[0092] Chromatographic conditions: Column: COSMOSIL C 18 (150mm×4.6mm); Mobile phase: potassium dihydrogen phosphate solution (0.5g / L phosphoric acid adjusted to pH 2.5±0.05): methanol = 40:60; Flow rate: 1.0mL min -1 ; Column temperature: 40℃; Detection wavelength: 251nm; Injection volume: 10μL; Detector: UV detector; Internal standard solution: Andrographolide concentration is 100μg / mL, prepared in methanol.

[0093] Take the plasma and homogenate of the heart, liver, spleen, lung, kidney, and trachea of ​​the rat, accurately measure 200 μL of blank biological sample, add internal standard stock solution, then add glacial acetic acid solution, vortex for 1 min, mix well, add 800 μL of acetonitrile, vortex for 5 min, mix well, and finally centrifuge at 8000 r / min for 8 min, remove 600 μL of the supernatant, blow dry with air. Redissolve the residue with 200 μL of methanol, sonicate for 30 s, centrifuge at 10000 r / min for 10 min, and take the supernatant for injection.

[0094] 36 SD rats were taken, and they were fasted for 12 hours before the experiment, and they were free to drink water. The rats were randomly divided into 2 groups, a tail vein injection group and a pulmonary administration group. The tail vein injection group was injected with a homemade chuanhuning solution at a dosage of 100 mg / kg, and the pulmonary administration group delivered the powder prepared in Example 12 to the rat lungs, and the dosage was set at 50 mg / kg. The tail vein injection group took blood and tissues after 0.08h, 0.17h, 0.34h, 0.50h, 1.00h, and 2.00h of administration; the pulmonary administration group took blood and tissues after 0.17h, 0.50h, 1.00h, 2.00h, 3.00h, and 4.00h of administration. The rats were killed by taking blood from the abdominal aorta at the above time points, and the blood obtained was placed in an EP tube with sodium heparin, centrifuged at 8000r / min for 8min, and the separated plasma was first stored in a -80℃ refrigerator. After blood was collected, the rat's heart, liver, spleen, lung, kidney, and trachea were dissected out, the blood stains on the tissue surface were washed off with physiological saline, the moisture on the tissue surface was absorbed with filter paper, and the bags were placed in self-sealing bags and placed in a -80°C refrigerator. The biological samples were subsequently processed, and the drug concentrations in plasma and tissues at each time point were measured and calculated.

[0095] The drug content in plasma and tissues under different administration methods was compared and analyzed by making time-drug content curves. The results are as follows: Fig.15 The time-drug content curve of drug distribution in each tissue is shown in Figure 2. Fig.16 As shown. By analyzing the drug-time curve, it can be seen that the different modes of administration have little effect on the drug content in plasma, heart, liver, spleen, and kidney, and mainly affect the drug distribution in the lungs and trachea. After 0.08h of tail vein administration, the blood drug concentration reached the maximum and was slightly higher than the blood drug concentration in the lung administration group, but the blood drug concentration after injection was maintained in the body for a short time and acted on the whole body, resulting in less drug distribution in the lungs; after lung administration, the drug amount in plasma was not much different from that in the tail vein administration group, but compared with the drug concentration in plasma, the concentration of the drug at the site of infection is considered to be more important. The drug content in the lungs of the lung administration group was significantly higher than that of the intravenous administration group, and the drug concentration in the lung tissue remained at a high level 4.00h after lung administration. At 4.00h in the lung administration group, the drug content in the lung tissue and trachea was 3.03 times and 4.12 times that in the tail vein injection group at 2.00h, respectively. By comparison, local lung administration increased the lung concentration of the drug and prolonged the drug's lung residence time. Compared with intravenous administration, pulmonary administration reduces the dosage, increases drug lung exposure, and improves patient compliance.

[0096] Embodiment 14

[0097] Due to the particularity of pulmonary drug delivery, particles with suitable particle size and easy dispersion can better enter the lungs. Spray-dried PDS powder is easy to aggregate and absorb moisture, and the properties of the powder are improved by adding excipients. The drug and excipients were spray-dried in a ratio of 1:1, and the powder was comprehensively analyzed from multiple aspects such as yield, particle size, tap density and hygroscopicity. The results are shown in Table 13.

[0098] Table 13 Effects of different excipients on Chuanhuning powder spray

[0099]

[0100] The drug was dissolved in aqueous solution with trehalose, glucose, mannitol and sorbitol and then spray-dried. The powder yield was extremely low and a large amount of powder adhered to the wall. The PDS raw material and the powders obtained by spray-drying with α-lactose monohydrate, leucine, glycine and alanine were analyzed. As can be seen from the table above, the powder yield obtained by spray-drying PDS with α-lactose monohydrate was higher, and the addition of α-lactose monohydrate significantly reduced the hygroscopicity of the powder. The addition of leucine, glycine and alanine resulted in a small difference in the yield, D[4,3] and Da values ​​of the powder; the addition of alanine increased the tap density of the dry powder, which was not conducive to the atomization performance of the dry powder. From the hygroscopicity data, it can be seen that leucine can reduce the hygroscopicity of the powder more. α-lactose monohydrate and leucine were selected as excipients.

[0101] For any person skilled in the art, without departing from the scope of the technical solution of the present invention, the technical content disclosed above can be used to make many possible changes and modifications to the technical solution of the present invention, or to modify it into an equivalent embodiment with equivalent changes. Therefore, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention should still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A Chuanhuning pulmonary inhalation powder for treating viral pneumonia, characterized in that: The invention comprises active ingredients and excipients, wherein the active ingredient is succinate, and the excipients comprise fillers, atomization enhancers and antistatic agents; the fillers comprise α-lactose monohydrate, trehalose, glucose, mannitol or xylitol; the atomization enhancers comprise leucine, alanine or glycine; and the antistatic agents are poloxamers.

2. The Chuanhuning pulmonary inhalation powder for treating viral pneumonia according to claim 1, characterized in that: The powder inhaler comprises, by weight volume (w / v), 0.5% to 1.4% of succinate, 0% to 0.45% of α-lactose monohydrate, 0.45% to 1.55% of leucine, 0.02% to 0.4% of poloxamer 188, and a total solid content of 1% to 5%.

3. The Chuanhuning pulmonary inhalation powder for treating viral pneumonia according to claim 2, characterized in that: The powder inhaler comprises, by weight volume (w / v), 0.5% to 1% of succinate, 0.1% to 0.3% of α-lactose monohydrate, 0.45% to 1.0% of leucine, 0.02% to 0.04% of poloxamer 188, and a total solid content of 1 to 3%.

4. The Chuanhuning pulmonary inhalation powder for treating viral pneumonia according to claim 2, characterized in that: The powder inhaler comprises, by weight volume (w / v), 0.5% of succinate, 0.1295% of α-lactose monohydrate, 0.4745% of leucine and 0.0200% of poloxamer; and the total solid content is 1.124%.

5. The Chuanhuning pulmonary inhalation powder for treating viral pneumonia according to any one of claims 1 to 3, characterized in that: The preparation method of the powder aerosol comprises: mixing and dissolving the active ingredient and the excipient raw materials in water, adjusting the pH to 5.0-7.0, and spray drying; the inlet temperature of the spray drying is 110-160° C., the feed rate is 4.5-9.0 mL / min, the pumping rate is 70-95%, and the gas flow rate is 586.25-921.25 L / h.

6. The Chuanhuning pulmonary inhalation powder for treating viral pneumonia according to claim 4, characterized in that: The inlet temperature of the spray drying was 120° C., the feed rate was 4.5 mL / min, the pumping rate was 95%, and the gas flow rate was 753.75 L / h.

7. Use of the Chuanhuning pulmonary inhalation powder according to any one of claims 1 to 4 in the preparation of a drug for treating viral pneumonia.

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