A lactose sieved inhalable powder formulation and a method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an inhalable powder preparation based on sieved lactose and a preparation method thereof. The inhalable powder preparation comprises the following raw materials in parts by weight: 1-1.25 parts of a pharmaceutical active ingredient, 55-60 parts of sieved lactose, 5-12 parts of modified lactose fine powder, 1-4 parts of hydroxypropyl-beta-cyclodextrin, and 1-3 parts of oleanolic acid beta-D-glucopyranosyl ester. The modified lactose fine powder is lactose fine powder grafted with palmitoyl chloride. The modification can weaken the formation ability of the lactose surface hydration layer, reduce the surface polarity, and produce steric hindrance, thereby significantly reducing the self-agglomeration tendency between the fine powder lactose, improving the combination characteristics of the fine powder lactose and the pharmaceutical particles, and further significantly improving the dispersion performance and lung deposition efficiency of the preparation. In addition, the combination of hydroxypropyl-beta-cyclodextrin and oleanolic acid beta-D-glucopyranosyl ester can significantly improve the stability of the preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a respirable powder preparation based on sieved lactose and a preparation method thereof. BACKGROUND

[0002] Dry powder inhalers (DPIs) have become a new favorite in the pulmonary drug delivery system due to their convenience in carrying and using and good stability of the preparation. DPIs refer to a drug delivery system in which a carrier and micronized drug or micronized drug is directly loaded into an inhalation device, and the drug particles are inhaled by the patient. Since the drug particles are small and have a large surface energy, they are prone to aggregation, which affects the stability and uniformity of the preparation. Therefore, a certain carrier is usually added to improve the flowability of the drug during the filling of the capsule and increase the dispersibility of the drug during the spraying or inhalation process.

[0003] Lactose is a carrier product approved by the FDA for inhalation administration, which is non-toxic, physiologically inert, does not harm the bioavailability of the drug, is chemically compatible with the drug, and can improve the flowability and dispersibility of the drug particles. Studies have shown that the addition of an appropriate amount of lactose fine powder (<10 μm) based on the use of coarse lactose particles (>50 μm) as the main carrier can further improve the performance of the preparation. The mechanism is that the complex of drug particles and lactose fine powder is more easily dispersed during atomization than pure drug particles. However, lactose fine powder is prone to self-aggregation due to its large specific surface area and strong hygroscopicity, which not only limits the full play of its function, but also leads to a decrease in drug loading due to competition for adsorption sites. In addition, drug fine powder has a small particle size and a large specific surface area, and belongs to a thermodynamically unstable system. There is a strong attractive force between particles, thereby increasing the probability of collision and making irreversible aggregation more likely to occur. Therefore, how to optimize the formulation composition to solve the above problems has become the key to improving the performance of dry powder inhalers. SUMMARY

[0004] In order to overcome the shortcomings of the prior art, the primary object of the present application is to provide a respirable powder preparation based on sieved lactose, which has good stability and lung targeting efficiency.

[0005] Another object of the present application is to provide a preparation method of the above-mentioned respirable powder preparation based on sieved lactose, which improves the performance of the dry powder inhaler based on sieved lactose.

[0006] The object of the present application is achieved by the following technical solutions:

[0007] An inhalable powder formulation based on sieved lactose comprises, by weight, the following raw materials: 1-1.25 parts of active pharmaceutical ingredient, 55-60 parts of sieved lactose, 5-12 parts of modified lactose powder, 1-4 parts of hydroxypropyl-β-cyclodextrin, and 1-3 parts of oleanolic acid β-D-glucopyranoyl ester.

[0008] The modified lactose fine powder is prepared as follows:

[0009]

[0010] Fine lactose powder was added to a mixed solution of N,N-dimethylformamide and triethylamine, cooled to -5 to 5°C, and then palmitoyl chloride was added and the reaction was maintained at this temperature. The reaction was then continued at room temperature. After the reaction was completed, the reaction solution was purified by column chromatography and recrystallized to obtain modified lactose. The modified lactose was then ground to obtain the fine modified lactose powder.

[0011] Furthermore, the ratio of lactose powder, palmitoyl chloride, dimethylformamide and triethylamine is 1 mmol: (1-1.12) mmol: (10-15) mL: (100-150) μL.

[0012] Furthermore, the heat preservation reaction time is 8-10 hours, and the reaction time continues after raising to room temperature for 10-12 hours.

[0013] Furthermore, the active pharmaceutical ingredient is a drug for treating lung diseases.

[0014] Furthermore, the drug for treating lung diseases is selected from one of sodium pyruvate, ciprofloxacin hydrochloride, or budesonide.

[0015] The above-mentioned method for preparing an inhalable powder formulation based on sieved lactose includes the following steps:

[0016] (1) Weigh each raw material according to the stated weight proportions; dissolve the active pharmaceutical ingredient in a solvent, add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranoyl ester and stir until homogeneous to obtain a mixed solution; spray dry the mixed solution to obtain pharmaceutical micro powder;

[0017] (2) Mix the drug micro powder with sieved lactose and modified lactose fine powder, and put the mixed powder into capsules, blister packs or dry powder inhalation devices to obtain the product.

[0018] Further, the solvent mentioned in step (1) is an aqueous solution of ethanol with a volume fraction of 30-50%.

[0019] Further, the spray drying conditions in step (2) are: inlet air temperature 130-160℃, outlet air temperature 75-85℃, atomization pressure 0.2-0.4MPa, feed rate 2.5-5mL / min, nozzle orifice diameter 0.7-1mm, and drying time 12-36h.

[0020] Furthermore, the mixing time in step (2) is 1 to 2 hours.

[0021] The present invention has the following advantages over the prior art:

[0022] 1. This invention provides an inhalable powder formulation based on sieved lactose, comprising modified lactose fine powder, hydroxypropyl-β-cyclodextrin, and oleanolic acid β-D-glucopyranoyl ester, among other raw materials. The modified lactose fine powder is palmitoyl chloride-grafted lactose fine powder. Through chemical modification, hydrophobic long chains are introduced onto the lactose surface. This modification weakens the ability of the lactose surface to form a hydration layer, reduces surface polarity, and generates steric hindrance, thereby significantly reducing the self-aggregation tendency between fine lactose particles and improving their binding characteristics with drug particles. This, in turn, significantly improves the dispersion performance and lung deposition efficiency of the formulation. The combined use of hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranoyl ester in the formulation significantly reduces the free energy of the drug particle system and improves the stability of the formulation. Simultaneously, the addition of oleanolic acid β-D-glucopyranoyl ester can effectively improve the lung targeting efficiency of the drug.

[0023] 2. The present invention also provides a method for preparing the above-mentioned inhalable powder formulation based on sieved lactose, which is simple in process and improves the performance of the powder formulation based on sieved lactose. Attached Figure Description

[0024] Figure 1 The figure shows the hydroxyproline content in the lung tissue of rats in each group of the experimental cases. Detailed Implementation

[0025] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0026] Example 1

[0027] An inhalable powder formulation based on sieved lactose, comprising, by weight, the following raw materials: 1.1 parts sodium pyruvate, 58 parts sieved lactose, 8 parts modified lactose powder, 3 parts hydroxypropyl-β-cyclodextrin (HP-β-CD), and 2 parts oleanolic acid β-D-glucopyranoyl ester (OAG).

[0028] The preparation method of the above-mentioned modified lactose fine powder is as follows:

[0029]

[0030] lactose powder (D) 90 After being fully dissolved in a mixed solution of N,N-dimethylformamide (12 mL) and triethylamine (120 μL) (5-10 μm, 1 mmol), the solution was cooled to 0 °C and then palmitoyl chloride (1.1 mmol) was added. The mixture was stirred at this temperature for 9 h, and then stirred at room temperature for 11 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was concentrated under reduced pressure, purified by column chromatography (chloroform / methanol, v / v = 6:1), and recrystallized from ethyl acetate-n-hexane to obtain modified lactose. The modified lactose was then ground to obtain modified lactose fine powder.

[0031] This embodiment also provides a method for preparing the above-mentioned inhalable powder formulation based on sieved lactose, the specific steps of which are as follows:

[0032] (1) Weigh each raw material according to the above weight proportions; fully dissolve sodium pyruvate in a 40% (v / v) ethanol aqueous solution, then add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranosyl ester and stir evenly to obtain a mixed solution; spray dry the mixed solution, set the inlet temperature to 145℃, the outlet temperature to 80℃, the atomization pressure to 0.3MPa, the feed rate to 3.5mL / min, the nozzle orifice diameter to 0.8mm, and the drying time to 12h to obtain drug micro powder;

[0033] (2) Mix the above-mentioned drug micro powder with sieved lactose and modified lactose fine powder for 2 hours, and fill the mixed powder into capsules to obtain the inhalable powder preparation based on sieved lactose.

[0034] Example 2

[0035] An inhalable powder formulation based on sieved lactose, comprising, by weight, the following raw materials: 1 part sodium pyruvate, 55 parts sieved lactose, 5 parts modified lactose powder, 1 part hydroxypropyl-β-cyclodextrin (HP-β-CD), and 3 parts oleanolic acid β-D-glucopyranoyl ester (OAG).

[0036] The preparation method of the above-mentioned modified lactose fine powder is as follows:

[0037] lactose powder (D) 90After being fully dissolved in a mixed solution of N,N-dimethylformamide (10 mL) and triethylamine (100 μL) (5-10 μm, 1 mmol), the solution was cooled to 0 °C and then palmitoyl chloride (1 mmol) was added. The mixture was stirred and kept at this temperature for 8 h, then stirred at room temperature for 10 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was concentrated under reduced pressure, purified by column chromatography (chloroform / methanol, v / v = 6:1), and recrystallized from ethyl acetate-n-hexane to obtain modified lactose. The modified lactose was then ground to obtain modified lactose fine powder.

[0038] This embodiment also provides a method for preparing the above-mentioned inhalable powder formulation based on sieved lactose, the specific steps of which are as follows:

[0039] (1) Weigh each raw material according to the above weight proportions; fully dissolve sodium pyruvate in a 30% (v / v) aqueous ethanol solution, then add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranosyl ester and stir evenly to obtain a mixed solution; spray dry the mixed solution with the following settings: inlet temperature 130℃, outlet temperature 75℃, atomization pressure 0.2MPa, feed rate 2.5mL / min, nozzle orifice diameter 0.7mm, and drying time 36h to obtain drug micro powder;

[0040] (2) Mix the above-mentioned drug micro powder with sieved lactose and modified lactose fine powder for 1 hour, and fill the mixed powder into capsules to obtain the inhalable powder preparation based on sieved lactose.

[0041] Example 3

[0042] An inhalable powder formulation based on sieved lactose, comprising, by weight, the following raw materials: 1.1 parts sodium pyruvate, 60 parts sieved lactose, 12 parts modified lactose powder, 4 parts hydroxypropyl-β-cyclodextrin (HP-β-CD), and 1 part oleanolic acid β-D-glucopyranoyl ester (OAG).

[0043] The preparation method of the above-mentioned modified lactose fine powder is as follows:

[0044] lactose powder (D) 90 The modified lactose was dissolved in a mixture of N,N-dimethylformamide (15 mL) and triethylamine (150 μL) to a concentration of 5-10 μm (1 mmol). After being cooled to 0 °C, palmitoyl chloride (1.12 mmol) was added, and the mixture was stirred at this temperature for 10 h. Then, the mixture was stirred at room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was concentrated under reduced pressure, purified by column chromatography (chloroform / methanol, v / v = 6:1), and recrystallized from ethyl acetate-n-hexane to obtain modified lactose. The modified lactose was then ground to obtain modified lactose fine powder.

[0045] This embodiment also provides a method for preparing the above-mentioned inhalable powder formulation based on sieved lactose, the specific steps of which are as follows:

[0046] (1) Weigh each raw material according to the above weight proportions; fully dissolve sodium pyruvate in a 50% (v / v) aqueous ethanol solution, then add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranosyl ester and stir evenly to obtain a mixed solution; spray dry the mixed solution with the following settings: inlet temperature 160℃, outlet temperature 85℃, atomization pressure 0.4MPa, feed rate 5mL / min, nozzle orifice diameter 1mm, and drying time 20h to obtain drug micro powder;

[0047] (2) Mix the above-mentioned drug micro powder with sieved lactose and modified lactose fine powder for 2 hours, and fill the mixed powder into capsules to obtain the inhalable powder preparation based on sieved lactose.

[0048] Comparative Example 1

[0049] The content of Comparative Example 1 is basically the same as that of Example 1, except that the modified lactose powder in Example 1 is replaced with lactose powder.

[0050] Comparative Example 2

[0051] Comparative Example 2 is basically the same as Example 1, except that oleanolic acid β-D-glucopyranoyl ester (OAG) in Example 1 is omitted.

[0052] Comparative Example 3

[0053] Comparative Example 3 is basically the same as Example 1, except that: oleanolic acid β-D-glucopyranoyl ester (OAG) in Example 1 is omitted, and hydroxypropyl-β-cyclodextrin (HP-β-CD) is increased to 5 parts.

[0054] Comparative Example 4

[0055] Comparative Example 4 is basically the same as Example 1, except that oleanolic acid β-D-glucopyranoyl ester (OAG) in Example 1 is replaced with oleanolic acid.

[0056] Experiment Example 1 Stability Test

[0057] The inhalable powder formulations prepared in Examples 1-3 and Comparative Examples 1-4 were tested for powder concentration (FPF) according to the methods specified in the Chinese Pharmacopoeia (2020 edition). The moisture content in the inhalable powder formulations was determined by the loss on drying method. The results are shown in Table 1. The inhalable powder formulations prepared in Examples 1-3 and Comparative Examples 1-4 were placed in a stability test chamber and stored at 40℃±2℃ and 75%±5% for 3 months. The FPF and moisture content were tested again, and the results are shown in Table 2.

[0058] Table 1

[0059]

[0060]

[0061] Table 2

[0062] Group FPF Moisture Example 1 60.5％ 0.47％ Example 2 61.6％ 0.42％ Example 3 60.2％ 0.58％ Comparative Example 1 39.0％ 2.51％ Comparative Example 2 43.7％ 2.82％ Comparative Example 3 46.6％ 3.24％ Comparative Example 4 49.1％ 3.68％

[0063] FPF refers to the effective dose of fine particles that can be deposited in the lungs under standard flow conditions. According to regulations, an FPF value greater than 12% indicates that the drug can be effectively deposited in the lungs. The higher the FPF, the higher the deposition rate of the drug in the lungs and the better the bioavailability.

[0064] Moisture content in inhalable powder formulations is a key indicator for assessing their quality stability and efficacy reliability. Increased moisture content can lead to powder hygroscopic agglomeration, reduced flowability, and affect the dosage accuracy of inhalable powder formulations. Moisture adsorbed on the particle surface increases interparticle adhesion, reduces dispersion efficiency during inhalation, resulting in decreased plasma flow factor (FPF) and reduced lung deposition.

[0065] As shown in Tables 1 and 2, the inhalable powder formulations prepared in Examples 1-3 of this invention have a maximum FPF value of 45.1%, indicating a high amount of drug that can be deposited in the lungs. Furthermore, after the inhalable powder formulations prepared in Examples 1-3 were placed at 40℃±2℃ and 75%±5% for 3 months, their FPF and moisture content did not change significantly, indicating that they have good stability.

[0066] Compared to Example 1, the inhalable powder formulations prepared in Comparative Examples 1-4 showed decreased FPF, increased moisture content, and poorer stability. This is likely because the present invention grafts palmitoyl chloride onto fine lactose powder, introducing hydrophobic long chains onto the lactose surface through chemical modification. This modification weakens the ability of lactose to form a hydration layer, reduces surface polarity, and creates steric hindrance, thereby significantly reducing the self-aggregation tendency between fine lactose particles and improving their binding characteristics with drug particles. Consequently, it significantly improves the dispersion performance and lung deposition efficiency of the formulation. Furthermore, the combined use of hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranoyl ester in the formulation significantly reduces the free energy of the drug particle system, improving the stability of the formulation.

[0067] Experimental Example 2

[0068] Ninety SPF-grade male SD rats (weighing 200-220g) were randomly divided into four groups: a blank control group, a model group, Examples 1-3, and Comparative Examples 1-4, with ten rats in each group. Rats were acclimatized for 3 days. All rats were anesthetized by intraperitoneal injection of 4% chloral hydrate (10mL / kg). The rats were then immobilized, their necks were shaved, and a longitudinal incision was made to expose the trachea. Except for the blank control group, in all other groups, a syringe was inserted 1cm into the trachea through the gap between the two tracheal cartilage rings towards the heart. After aspiration without resistance, bleomycin (4mg / kg) was injected into the trachea. The blank control group received an equal volume of physiological saline. The incision was immediately sutured and disinfected after injection. The rat board was then rotated upright for 3 minutes to ensure even drug distribution in the lungs, thus establishing a pulmonary fibrosis model.

[0069] Starting the day after modeling, groups 1-3 and comparative groups 1-4 were given the drug via nebulized inhalation at a dose of 0.8 mg / kg (based on the mass of sodium pyruvate), once daily for 28 consecutive days; the blank control group and the model group were given an equal volume of physiological saline via nebulized inhalation.

[0070] Twenty-four hours after the last administration, rats in each group were anesthetized by intraperitoneal injection of 50 mg / kg of salbutamol. After anesthesia, endotracheal intubation was performed, and the rats were connected to a small animal pulmonary function analyzer to measure pulmonary function indicators in each group: inspiratory capacity (IC), dynamic lung compliance (Cdyn), and forced expiratory flow rate (FEF) at 10% of exhaled FVC. 50％ The results are shown in Table 3. After pulmonary function testing, rats in each group were sacrificed, and lung tissue was extracted. The hydroxyproline content in the lung tissue was detected by enzyme-linked immunosorbent assay (ELISA). The results are shown in Table 3. Figure 1 .

[0071] Table 3. Lung function indicators of rats in each group

[0072]

[0073] From Table 3 and Figure 1 It can be seen that, compared with the blank control group, the model group rats had higher inspiratory volume, dynamic lung compliance, and FEF. 50％ Significantly reduced, and significantly increased hydroxyproline content in lung tissue. Compared with the model group, the inspiratory volume, dynamic lung compliance, and FEF of rats in Examples 1-3 were significantly reduced. 50％ Significantly increased, while hydroxyproline content in lung tissue significantly decreased, whereas in control groups 1 and 2 rats showed significantly increased inspiratory volume, dynamic lung compliance, and FEF. 50％ The increase in hydroxyproline content and the decrease in hydroxyproline content in lung tissue were both relatively small. These results indicate that the inhalable powder formulation based on sieved lactose prepared in this invention has an improving effect on respiratory function in rats with pulmonary fibrosis.

[0074] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.

Claims

1. An inhalable powder formulation based on sieved lactose, characterized in that, The product comprises, by weight, the following raw materials: 1-1.25 parts of active pharmaceutical ingredient, 55-60 parts of sieved lactose, 5-12 parts of modified lactose powder, 1-4 parts of hydroxypropyl-β-cyclodextrin, and 1-3 parts of oleanolic acid β-D-glucopyranoyl ester; wherein the active pharmaceutical ingredient is sodium pyruvate. The modified lactose fine powder is prepared as follows: Fine lactose powder was added to a mixed solution of N,N-dimethylformamide and triethylamine, cooled to -5 to 5°C, palmitoyl chloride was added and the reaction was maintained at this temperature, and then the temperature was raised to room temperature to continue the reaction. After the reaction was completed, the reaction solution was purified by column chromatography and recrystallized to obtain modified lactose. Modified lactose is ground to obtain the modified lactose fine powder; The method for preparing the inhalable powder formulation based on sieved lactose includes the following steps: (1) Weigh each raw material according to the stated weight proportions; dissolve the active pharmaceutical ingredient in a solvent, add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranoyl ester and stir until homogeneous to obtain a mixed solution; spray dry the mixed solution to obtain pharmaceutical micro powder; (2) Mix the drug micro powder with sieved lactose and modified lactose fine powder, and put the mixed powder into capsules, blister packs or dry powder inhalation devices to obtain the product.

2. The inhalable powder formulation based on sieved lactose according to claim 1, characterized in that, The ratio of lactose powder, palmitoyl chloride, N,N-dimethylformamide and triethylamine is 1 mmol: (1-1.12) mmol: (10-15) mL: (100-150) μL.

3. The inhalable powder formulation based on sieved lactose according to claim 1, characterized in that, The heat preservation reaction takes 8–10 hours, and the reaction continues at room temperature for 10–12 hours.

4. The method for preparing the inhalable powder formulation based on sieved lactose according to any one of claims 1 to 3, characterized in that, Includes the following steps: (1) Weigh each raw material according to the stated weight proportions; dissolve the active pharmaceutical ingredient in a solvent, add hydroxypropyl-β-cyclodextrin and oleanolic acid β-D-glucopyranoyl ester and stir until homogeneous to obtain a mixed solution; spray dry the mixed solution to obtain pharmaceutical micro powder; (2) Mix the drug micro powder with sieved lactose and modified lactose fine powder, and put the mixed powder into capsules, blister packs or dry powder inhalation devices to obtain the product.

5. The method for preparing an inhalable powder formulation based on sieved lactose according to claim 4, characterized in that, The solvent mentioned in step (1) is an aqueous solution of ethanol with a volume fraction of 30-50%.

6. The method for preparing an inhalable powder formulation based on sieved lactose according to claim 4, characterized in that, The conditions for spray drying in step (1) are: inlet air temperature 130-160℃, outlet air temperature 75-85℃, atomization pressure 0.2-0.4 MPa, feed rate 2.5-5 mL / min, nozzle orifice diameter 0.7-1 mm, and drying time 12-36 h.

7. The method for preparing an inhalable powder formulation based on sieved lactose according to claim 4, characterized in that, The mixing time in step (2) is 1 to 2 hours.

Images