Particles for large-dose water-soluble drug inhalation powder inhalation and preparation method thereof

Abstract

The invention relates to particles for large-dose water-soluble drug inhalation powder and a preparation method of the particles, and belongs to the technical field of medicines. The preparation method of the particles for the large-dose water-soluble drug inhalation powder inhalation is characterized in that the preparation method of the particles is a spray drying method and specifically comprises the following steps: introducing a water-soluble polymer material or a water-soluble high-glass-transition-temperature material into a spray-dried feeding solution containing a water-soluble pharmaceutical active substance; drug-loaded particles are obtained by controlling a spray drying process. The preparation method of the particles for improving the moisture absorption stability of the large-dose water-soluble drug inhalation powder inhalation is suitable for various water-soluble drugs, and is especially suitable for drugs which are unstable when encountering moisture, are large in treatment dose and have concentration-dependent curative effects.

Description

Technical Field

[0001] The invention relates to particles for large-dose water-soluble drug inhalation powder and a preparation method thereof, belonging to the technical field of medicine. Background Art

[0002] Commonly used pulmonary drug delivery dosage forms mainly include inhalation sprays, inhalation aerosols and inhalation powder inhalers (DPI). Inhalation powder inhalers combine particle preparation technology with drug delivery devices, and use the patient's inhaled airflow to depolymerize the powder, which greatly improves the coordination of patient medication and can significantly increase the lung deposition rate of drug particles. Inhalation powder inhalers do not require propellants, have superior chemical stability compared to solution preparations, are simple to operate, easy to carry, and have high patient compliance. Compared with carrier-based DPIs based on physical mixing, some drugs must be delivered in a carrier-free form to meet the requirements for delivery doses. Based on the particle engineering strategy, only a small amount of excipients need to be added to the prescription to change the microstructure of the particles, making them have stable aerosol properties, which is very beneficial for the delivery of large doses of drugs. Based on a deep understanding of the particle formation process, particle engineering technology has achieved remarkable success in the development of carrier-free DPI products. Technologies that can be used to prepare engineered particles include spray drying, spray freeze drying, freeze drying, thin film freeze drying, supercritical fluid technology, etc.

[0003] Spray drying technology is a process that can complete the preparation from feed liquid to solid particles in one step, and the operation is very simple. By adjusting the properties of the feed solution and process parameters, the particle characteristics can be flexibly controlled, including the shape, particle size, density and surface properties of the particles. By regulating the heat and mass transfer process to adjust the microstructure of the particles, spray drying technology can meet various requirements for particle structure.

[0004] However, after spray drying, pharmaceutically active substances may exist in an amorphous form, which increases the drug's sensitivity to moisture and affects the stability of the particles. For most amorphous spray-dried particles, on the one hand, the adsorption and removal of moisture will cause local dissolution and recrystallization of the particles, leading to irreversible aggregation; on the other hand, moisture will plasticize the amorphous material, causing a significant decrease in the glass transition temperature, bringing stability problems. For the design of inhalation powders for large doses of water-soluble drugs, in order to meet the drug delivery requirements, it is necessary to reduce the amount of excipients added in the prescription as much as possible. Therefore, they also face the dual challenges of drug delivery dose and moisture-proof stability.

[0005] Drying starts instantaneously after the atomization of the feed solution. The evaporation rate of the solvent and the diffusion rate of the solute within the droplet are important parameters that determine the radial distribution of the solute in the particles. When the Péclet number (Pe) of the solute is relatively large, the recession rate at the droplet surface will be faster than the diffusion rate of the solute towards the core. The concentration of the solute at the surface is much higher than that at the core, enabling surface enrichment. For hydrophobic excipients, due to their low solubility in water, regardless of whether the selected solvent is water or an organic solvent, the rapid evaporation of the solvent will cause it to reach supersaturation faster at the shrinking surface of the droplet and accumulate on the surface, forming a hydrophobic outer shell with a moisture-proof protection effect. However, for water-soluble drugs for large-dose delivery, a dense hydrophobic surface is not conducive to the rapid release of the drug from the interior of the particles. Water-soluble polymer materials have a relatively high molecular weight themselves, and their molecules have a low mobility and a high Péclet number within the atomized droplets. Therefore, forming a hydrophilic film on the outer surface of the pharmaceutically active substance is a solution to improve the wet stability of the particles without affecting drug release.

[0006] In addition, due to the rapid evaporation of the solvent during the drying process, the molecules will be disordered and in a thermodynamically unstable amorphous state. The weak intermolecular binding force makes it easier for them to absorb water from the environment and be plasticized, resulting in a decrease in the glass transition temperature of the formulation. Therefore, another solution to the water plasticization effect is to form a protective glass matrix around the pharmaceutically active substance to hinder molecular movement and increase the glass transition temperature of the formulation. Summary of the Invention

[0007] The objective of the present invention is to overcome the unsatisfactory wet stability of inhalable powder aerosols prepared by the current spray drying process, and to provide a preparation method for spray-dried drug-loaded particles that uses different types of water-soluble materials to improve the wet stability of the particles.

[0008] A preparation method for particles for a large-dose water-soluble drug inhalable powder aerosol, wherein the preparation method of the particles is the spray drying method, specifically: introducing a water-soluble polymer material or a water-soluble material with a high glass transition temperature into a feed solution containing a water-soluble pharmaceutically active substance during spray drying, and obtaining drug-loaded particles by controlling the spray drying process, wherein,

[0009] The water-soluble polymer material is a pharmaceutically acceptable natural polymer material, semi-synthetic polymer material or synthetic polymer material;

[0010] Furthermore, the water-soluble polymer material includes one or more of chitosan, dextran, pectin, xanthan gum, sodium hyaluronate, sodium alginate, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol, preferably sodium hyaluronate.

[0011] The water-soluble high glass transition temperature materials include one or more of lactose, sucrose, trehalose, raffinose, mannitol, pullulan, inulin, gum arabic, polyvinyl alcohol, and polyglycolic acid; preferably trehalose or pullulan.

[0012] Furthermore, the molecular weight of the water-soluble polymer material is 1 - 500 kDa, and the preferred molecular weight range is 25 - 400 kDa.

[0013] The feed solution described in the present invention is composed of water, a water-soluble pharmaceutically active substance, a water-soluble polymer material, or a water-soluble high glass transition temperature material.

[0014] Furthermore, the concentration of the water-soluble pharmaceutically active substance in the feed solution is 1 - 10 mg / ml.

[0015] Furthermore, the water-soluble polymer material accounts for 5 wt.% - 40 wt.% of the formulation (the sum of the water-soluble pharmaceutically active substance and the water-soluble polymer material).

[0016] Furthermore, the water-soluble high glass transition temperature material accounts for 3 - 70 wt.%, preferably 5 - 40 wt.%, of the formulation (the sum of the water-soluble pharmaceutically active substance and the water-soluble high glass transition temperature material).

[0017] Furthermore, the spray drying process has an inlet temperature range of 100 - 150 °C, a feed rate range of 0.3 - 30 mL / min, and an air intake rate range of 246 - 742 L / h.

[0018] As used herein, the "water-soluble drug" refers to a drug that can be completely dissolved in 1 - 100 ml of water for injection per 1 gram of the drug. For example, ciprofloxacin hydrochloride, tobramycin sulfate, amikacin sulfate, salbutamol sulfate, terbutaline sulfate, isoniazid, colistin sulfate, pyrazinamide, kanamycin sulfate, roflumilast, octreotide acetate, netilmicin sulfate, sodium cromoglycate, amphotericin B, ipratropium bromide, glycopyrronium bromide, exenatide, semaglutide, liraglutide, insulin (in acidic conditions), acetylcysteine, ribavirin, zanamivir, levosalbutamol hydrochloride, aclidinium bromide, etc.

[0019] As used herein, the "high dose" refers to a single dose of the drug for pulmonary inhalation that is greater than 2 mg when exerting its pharmacological effect.

[0020] As used herein, the "high-dose water-soluble drug" specifically includes biopolymers, small molecule chemical drugs, traditional Chinese medicine monomers, and diagnostic drugs.

[0021] The method of the present invention prepares an inhalation powder aerosol of a large-dose water-soluble drug that is stable in a wet environment by changing the composition and spray-drying process conditions, which can significantly increase the pulmonary deposition of the drug and has wide applications in pulmonary drug delivery.

[0022] A preferred technical solution of the present invention is as follows:

[0023] A method for preparing particles for a large-dose water-soluble drug inhalation powder aerosol, the method comprising the following steps:

[0024] a. Add a water-soluble polymer material or a water-soluble material with a high glass transition temperature to distilled water and stir magnetically at room temperature until completely dissolved;

[0025] b. Add a water-soluble pharmaceutically active substance to the solution obtained in step a and stir magnetically at room temperature until completely dissolved to obtain a spray-drying feed solution;

[0026] c. After the mixture in step b is stirred evenly, perform spray-drying treatment on it to obtain the drug-loaded particles of the corresponding pharmaceutically active substance. The inlet temperature range during the spray-drying process is 100-150 °C, the feed rate range is 0.3-30 mL / min, and the inlet air rate range is 246-742 L / h.

[0027] Another object of the present invention is to provide particles for a water-soluble drug inhalation powder aerosol prepared by the above method.

[0028] A particle for a large-dose water-soluble drug inhalation powder aerosol, wherein a polymer coating film is wrapped on the surface of the particle, and the polymer coating film formed on the surface of the pharmaceutically active substance inhalation particle is composed of a water-soluble polymer material.

[0029] A particle for a large-dose water-soluble drug inhalation powder aerosol, wherein the particle uses a material with a high glass transition temperature as a glass matrix, and the pharmaceutically active substance is uniformly dispersed in the glass matrix.

[0030] Preferably, the particles for the inhalation powder aerosol are nearly spherical, and the aerodynamic particle size range is 0.5-10 μm, preferably the aerodynamic particle size is 1-5 μm.

[0031] The beneficial effects of the present invention are as follows: The method for preparing particles for improving the hygroscopic stability of a large-dose water-soluble drug inhalation powder aerosol of the present invention can significantly improve the physical stability and atomization and dispersion performance of the drug in a high-humidity environment. After exposure to a high-humidity environment of 25±2 °C / 75±5% RH, the powder has good dispersibility, and there are no significant differences in particle size and in vitro aerodynamic behavior within 4 h. The method for preparing particles for improving the hygroscopic stability of a large-dose water-soluble drug inhalation powder aerosol provided by the present invention is suitable for various water-soluble drugs, especially for drugs that are unstable in the presence of moisture, have a large therapeutic dose, and have a concentration-dependent efficacy. Description of the Drawings

[0032] Figure 1 is the enrichment ratio of the water-soluble polymer on the surface of the spray-dried particles prepared in Examples 1-3;

[0033] Figure 2 is the anti-humidity absorption performance result of the spray-dried particles prepared in Examples 1-3;

[0034] Figure 3 is the anti-humidity absorption performance result of the spray-dried particles prepared in Examples 10-12. Detailed Description of the Invention

[0035] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way.

[0036] In the following examples, the test methods are all conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0037] One of the specific embodiments:

[0038] A method for preparing particles for improving the moisture absorption stability of a large-dose water-soluble drug inhalation powder aerosol. The feed solution for spray drying introduces a water-soluble polymer material or a water-soluble high glass transition temperature material on the basis of containing a water-soluble pharmaceutically active substance, and drug-loaded particles with stronger wet stability are obtained by controlling the spray drying process.

[0039] The specific content is as follows:

[0040] The particle preparation method is spray drying, and a polymer film is formed on the particle surface by adjusting the formulation composition or the preparation process conditions to play a moisture-proof protection role; the polymer film formed on the surface of the inhaled particles by the spray drying process technology is composed of a water-soluble polymer material.

[0041] The particle preparation method is spray drying, and the glass transition temperature of the inhalable particles is increased to improve the wet stability of the inhalable particles; the particles use a high glass transition temperature material as the glass matrix, and the pharmaceutically active substance is uniformly dispersed in the glass matrix. The water-soluble polymer material refers to pharmaceutically recognized natural polymer materials, semi-synthetic polymer materials and synthetic polymer materials, including one or more of chitosan, dextran, pectin, xanthan gum, sodium hyaluronate, sodium alginate, sodium carboxymethyl cellulose, polyvinylpyrrolidone and polyvinyl alcohol, and preferably sodium hyaluronate;

[0042] The molecular weight of the water-soluble polymer material is 1-500 kDa, and the preferred molecular weight range is 25-400 kDa;

[0043] The addition amount range of the water-soluble polymer material in the formulation is 5%-40% (w / w).

[0044] In addition, by adding a water-soluble material with a high glass transition temperature to the formulation to form a protective glass matrix, the wet stability of the inhaled particles can be significantly improved.

[0045] The water-soluble material with a high glass transition temperature includes, but is not limited to, one or more of lactose, sucrose, trehalose, raffinose, mannitol, pullulan, inulin, gum arabic, polyvinyl alcohol, and polyglycolic acid. Trehalose and pullulan are preferred;

[0046] The addition amount range of the water-soluble material with a high glass transition temperature in the formulation is 3-70% (w / w), preferably 5-40% (w / w).

[0047] The inhaled powder aerosol particles are nearly spherical, and the aerodynamic particle size range is 0.5-10 μm, preferably the aerodynamic particle size is 1-5 μm.

[0048] The performance parameters of the products in the following examples and comparative examples were all measured by the following methods.

[0049] 1. Median diameter D50 and volume mean diameter D[4,3]: Measured using a laser particle size analyzer (Sympatec HELOS / KF).

[0050] 2. Fine particle fraction (FPF) and emitted fraction (EF): Measured using a next-generation pharmaceutical impactor (Copley Scientific).

[0051] Example 1: 95Tob5H-HA

[0052] Weigh appropriate amounts of tobramycin sulfate (Tob) and sodium hyaluronate (HA) respectively, add 100 mL of deionized water thereto to prepare a drug-containing solution containing 95% (w / w) Tob and 5% (w / w) HA at a concentration of 10 mg / mL (the total concentration of Tob and HA in the drug-containing solution, and the same meaning applies to other examples). Among them, the molecular weight of sodium hyaluronate is 350 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0053] The surface of the particles prepared by spray drying was analyzed by X-ray photoelectron spectroscopy (XPS) using a 250Xi photoelectron spectrometer, and the sampling depth was between 1 - 10 nm. The distribution of excipients / drugs on the particle surface was semi-quantitatively interpreted using the atomic concentrations of each element. To calculate the relative percentages of HA and Tob on the surface of the composite particles, reference data were obtained from the two compounds, and then the data in the composite particles were compared with the reference data. The mass percentage of HA was estimated as follows: Assume that the atomic concentration of each element in the composite particles is a linear combination of the corresponding concentrations in the pure compounds, and is appropriately scaled and normalized using the number of respective atoms in the compound molecules. Since Na is the only element for HA and S is the only element for Tob. Therefore, the mole fraction of the compound can be deduced from the corresponding element concentration, and then its mass fraction on the particle surface can be estimated (as shown in the following formula).

[0054]

[0055] In the formula, x HA , x Tob represent the mole fractions of HA and Tob respectively, M HA , M Tob represent the molecular weights of HA and Tob respectively. Therefore, after estimating the mass fraction of the compound on the particle surface using the atomic concentration on the particle surface, comparing it with the compound content in the feed liquid, the increase multiple of its concentration on the particle surface compared to the concentration of HA in the feed liquid can be obtained.

[0056] Example 2: 85Tob15H-HA

[0057] Appropriate amounts of tobramycin sulfate (Tob) and sodium hyaluronate (HA) were weighed respectively, and 100 mL of deionized water was added thereto to prepare a drug-containing solution containing 85% (w / w) Tob and 15% (w / w) HA at a concentration of 10 mg / mL. Among them, the molecular weight of sodium hyaluronate was 350 kDa. The above solution was spray-dried, and the process parameters were: inlet temperature ≈ 110 °C, feed rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0058] Example 3: 60Tob40H-HA

[0059] Weigh appropriate amounts of tobramycin sulfate (Tob) and sodium hyaluronate (HA) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 60% (w / w) Tob and 40% (w / w) HA. Among them, the molecular weight of sodium hyaluronate is 350 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0060] Example 4: 60Tob40L-HA

[0061] Weigh appropriate amounts of tobramycin sulfate (Tob) and sodium hyaluronate (HA) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 60% (w / w) Tob and 40% (w / w) HA. Among them, the molecular weight of sodium hyaluronate is 50 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0062] Example 5: 60Tob40M-HA

[0063] Weigh appropriate amounts of tobramycin sulfate (Tob) and sodium hyaluronate (HA) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 60% (w / w) Tob and 40% (w / w) HA. Among them, the molecular weight of sodium hyaluronate is 100 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0064] Example 6: 85Tob15SA

[0065] Weigh appropriate amounts of tobramycin sulfate (Tob) and sodium alginate (SA) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) Tob and 15% (w / w) sodium alginate. Among them, the molecular weight of sodium alginate is 50 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0066] Example 7: 85Tob15CTS

[0067] Weigh appropriate amounts of tobramycin sulfate (Tob) and chitosan (CTS), and add 100 mL of deionized water to them to prepare a 10 mg / mL drug-containing solution containing 95% (w / w) Tob and 5% (w / w) chitosan. Among them, the molecular weight of sodium alginate is 25 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0068] Example 8:

[0069] The difference between this example and Example 1 is: feeding rate ≈ 4.5 mL / min, and others are the same.

[0070] Example 9:

[0071] The difference between this example and Example 1 is: gas flow rate ≈ 414 L / h, and others are the same.

[0072] Example 10: 100 Tob

[0073] Weigh appropriate amounts of tobramycin sulfate (Tob), and add 100 mL of deionized water to it to prepare a tobramycin sulfate solution containing 10 mg / mL. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0074] Example 11: 100 SS

[0075] Weigh appropriate amounts of salbutamol sulfate (SS), and add 100 mL of deionized water to it to prepare a salbutamol sulfate solution containing 10 mg / mL. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0076] Example 12: 85 SS 15 HA

[0077] Weigh appropriate amounts of salbutamol sulfate (SS) and sodium hyaluronate (HA) respectively, and add 100 mL of deionized water to them to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) SS and 15% (w / w) HA. Among them, the molecular weight of sodium hyaluronate is 50 kDa. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0078] I. Study on the enrichment amount of water-soluble polymer on the surface of spray-dried particles

[0079] The basic properties of the spray-dried particles obtained in Examples 1, 8, 9, and 10 and the enrichment amount of the water-soluble polymer on the particle surface were characterized. The results are shown in Table 1 below. As can be seen from Table 1, the particle size and the theoretical aerodynamic diameter of the spray-dried drug-loaded particles prepared in Example 1 are both within the ideal range. Comparing Example 1 and Example 10, it can be seen that adding HA to the formulation will significantly affect the particle size and the tapped density of the spray-dried particles under the same spray-drying conditions. In addition, comparing Examples 1, 8, and 9, it can be seen that when the preparation conditions change, it will cause changes in the particle size and the tapped density of the spray-dried particles, thereby changing the aerodynamic particle size of the dry powder inhaler, but all within the inhalable range.

[0080] Table 1 Characterization of the particle properties of Examples 1, 8, 9, and 10

[0081]

[0082] Taking the spray-dried drug-loaded particles prepared in Example 1 as an example, the enrichment amount of the water-soluble polymer HA on the particle surface is 18.9 times that of HA at the formulation concentration (i.e., theoretically, the concentration on the particle surface should be 5%, w / w). Correspondingly, the enrichment amounts of HA on the surfaces of the spray-dried drug-loaded particles prepared in Examples 8 and 9 are 9.6 times and 17.3 times the concentration of HA in the formulation, respectively.

[0083] The results of the sodium hyaluronate content on the surfaces of the particles in Examples 1-3 are as Figure 1 shown. As the addition ratio of sodium hyaluronate increases, the sodium hyaluronate content on the particle surface gradually increases. This indicates that an increase in concentration is beneficial to the enrichment of sodium hyaluronate on the surface of the spray-dried particles.

[0084] II. Study on the anti-humidity absorption performance and particle stability of the water-soluble polymer-coated spray-dried particles

[0085] After exposing the drug-loaded formulations, the raw / processed excipients and the active pharmaceutical ingredient in Examples 1-3 to a high-humidity environment of 75% RH / 25 ± 2 °C, samples were taken at specific time points and weighed to calculate the percentage of moisture absorption. The moisture absorption curve is as Figure 2 shown. The results show that the moisture absorption of all formulations reaches equilibrium at 24 h and no longer increases. As the sodium hyaluronate content in the formulation increases, the moisture absorption of the drug-loaded particles shows a trend of first increasing and then decreasing. This indicates that when the sodium hyaluronate content in the formulation reaches 15% (w / w), the integrity of the sodium hyaluronate film has reached the protection requirement and can reduce the particle moisture absorption rate.

[0086] The particle sizes of the spray-dried granules prepared in Examples 11 and 12 were measured after storage at 75% RH / 25 ± 2 °C for 4 h. The results are shown in Table 2 below. Compared with the spray-dried formulation containing only the drug, the water-soluble polymer-coated spray-dried granules can play a role in maintaining the particle stability.

[0087] Table 2 High-humidity stability results of the spray-dried granules prepared in Example 10 and Example 11

[0088]

[0089] Example 13: 95Tob5Pull

[0090] Appropriate amounts of tobramycin sulfate (Tob) and pullulan (Pull) were weighed separately and 100 mL of deionized water was added thereto to prepare a 10 mg / mL drug-containing solution containing 95% (w / w) Tob and 5% (w / w) Pull. The above solution was spray-dried, and the process parameters were: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0091] Example 14: 85Tob15Pull

[0092] Appropriate amounts of tobramycin sulfate (Tob) and pullulan (Pull) were weighed separately and 100 mL of deionized water was added thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) Tob and 15% (w / w) pullulan. The above solution was spray-dried, and the process parameters were: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0093] Example 15: 60Tob40Pull

[0094] Appropriate amounts of tobramycin sulfate (Tob) and pullulan (Pull) were weighed separately and 100 mL of deionized water was added thereto to prepare a 10 mg / mL drug-containing solution containing 60% (w / w) Tob and 40% (w / w) pullulan. The above solution was spray-dried, and the process parameters were: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0095] Example 16: 85Tob15Tre

[0096] Weigh appropriate amounts of tobramycin sulfate (Tob) and trehalose (Tre) respectively, add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) Tob and 15% (w / w) trehalose. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0097] Example 17: 70Tob30Inulin

[0098] Weigh appropriate amounts of tobramycin sulfate (Tob) and inulin respectively, add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 70% (w / w) Tob and 30% (w / w) inulin. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0099] Example 18: 85Tob15Aca

[0100] Weigh appropriate amounts of tobramycin sulfate (Tob) and arabic gum (Aca) respectively, add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) Tob and 15% (w / w) arabic gum. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0101] Example 19: 85SS15Pull

[0102] Weigh appropriate amounts of salbutamol sulfate (SS) and pullulan (Pull) respectively, add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) salbutamol sulfate and 15% (w / w) Pull. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0103] Example 20: 100AS

[0104] Weigh appropriate amounts of amikacin sulfate (AS) respectively, add 100 mL of deionized water thereto to prepare a 10 mg / mL amikacin sulfate solution. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0105] Example 21: 85AS15Pull

[0106] Weigh appropriate amounts of amikacin sulfate (AS) and pullulan (Pull) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) amikacin sulfate and 15% (w / w) pullulan. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0107] Example 22: 85Oct15Tre

[0108] Weigh appropriate amounts of octreotide acetate (Oct) and trehalose (Tre) respectively, and add 100 mL of deionized water thereto to prepare a 10 mg / mL drug-containing solution containing 85% (w / w) amikacin sulfate and 15% (w / w) trehalose. Spray-dry the above solution, and the process parameters are: inlet temperature ≈ 110 °C, feeding rate ≈ 3 mL / min, gas flow rate ≈ 536 L / h, and air extraction rate 100%.

[0109] III. Study on the anti-hygroscopicity and particle stability of spray-dried particles containing a water-soluble carrier with a high glass transition temperature

[0110] Measure the particle size of the spray-dried particles prepared in Examples 13, 14, and 15 after storing them at 75% RH / 25 ± 2 °C for 4 h. The results are shown in Table 3 below. The results show that with the increase in the content of pullulan, the stability of the preparation is significantly improved, and the drug-loaded particles can be maintained stable in a high-humidity environment for 4 h.

[0111] Draw the moisture absorption curve as Figure 3 shown. The results show that the moisture absorption rate of the drug-loaded particles decreases with the increase in the content of pullulan in the formulation.

[0112] Table 3 High-humidity stability results of the spray-dried particles prepared in Examples 13 - 15

[0113]

[0114]

[0115] The particle sizes of the spray-dried granules prepared in Example 16 and Example 18 were measured after storing at 75% RH / 25 ± 2 °C for 4 h, and the results are shown in Table 4 below. Both formulations have great potential for maintaining the stability of the granules under high humidity conditions. The particle sizes of the spray-dried granules prepared in Example 11, 19 were measured after storing at 75% RH / 25 ± 2 °C for 4 h, and the results are shown in Table 4 below. For different large-dose water-soluble drugs, the spray-dried granules containing water-soluble carriers with high glass transition temperatures can all play a role in anti-humidity absorption.

[0116] Table 4 High humidity stability results of the spray-dried granules prepared in Examples 13 and 17, 11 and 19

[0117]

[0118] IV. Evaluation of Aerodynamic Behavior

[0119] The aerodynamic behaviors of two formulations, 85Tob15L-HA prepared in Example 2 and 85Tob15Pull prepared in Example 11, were investigated. A new generation impactor NGI (Copley Scientific, UK) equipped with an artificial larynx and a pre-separator was used for measurement. The measuring device was also equipped with a flow controller (Copley TPK 2000), a flow display meter (Copley DFM2000), and a vacuum pump (Copley HCP5). According to the requirements of the Chinese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia, when measuring the in vitro aerodynamic deposition distribution of inhaled powder aerosols, the air flow velocity is sufficient to generate a pressure difference of 4 kPa in the inhalation device. The inhalation device used in this study was (Teva Pharmaceuticals, Netherlands), with a flow rate of 100 L / min and a duration of 2.4 s to ensure an air volume of 4 L.

[0120] The aerodynamic behaviors of the granules prepared in Example 2 (85Tob15L-HA) and Example 14 (85Tob15Pull) were investigated after exposure to an environment of 75 ± 5% RH / 25 ± 2 °C for 0 or 4 h. The in vitro atomization performance results of all spray-dried granules are shown in Table 5 below. The results show that the prepared granules can significantly improve the anti-humidity stability. It may be affected by the moisture in the environment, resulting in a decrease in the electrostatic force of the granules, and the granules are more easily dispersed. The FPF values of each group after storing at high humidity for 4 h show an upward trend, but there is no statistical difference. It shows that the particle preparation technology described in the present invention can significantly improve the anti-humidity performance of the granules and reduce the cohesion between the granules, thereby improving the pulmonary delivery efficiency of the drug.

[0121] Table 5 Influence of high humidity on the atomization deposition behavior of the spray-dried granules prepared in Example 2 and Example 14

[0122]

[0123] In summary, the particle preparation method of the present invention for preparing an inhalable powder using a water-soluble material can improve the hygroscopic stability of an inhalable powder of a high-dose water-soluble drug represented by tobramycin sulfate, and at the same time meet the dual requirements of drug delivery dose and wet stability.

Claims

1. A method for preparing particles for large-dose water-soluble drug inhalation powder, characterized in that: The preparation method of the particles is a spray drying method, specifically: introducing a water-soluble polymer material or a water-soluble high glass transition temperature material into a feed solution containing a water-soluble pharmaceutically active substance for spray drying, and obtaining drug-loaded particles by controlling the spray drying process, wherein: The water-soluble polymer material is a pharmaceutically usable natural polymer material, a semi-synthetic polymer material or a synthetic polymer material; The water-soluble high glass transition temperature material includes one or more of lactose, sucrose, trehalose, raffinose, mannitol, pullulan, inulin, gum arabic, polyvinyl alcohol and polyglycolic acid; preferably trehalose or pullulan.

2. The method according to claim 1, characterized in that The water-soluble polymer material includes one or more of chitosan, dextran, pectin, xanthan gum, sodium hyaluronate, sodium alginate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and polyvinyl alcohol, preferably sodium hyaluronate.

3. The method according to claim 1, characterized in that The molecular weight of the water-soluble polymer material is 1-500 kDa, preferably in the range of 25-400 kDa.

4. The method according to claim 1, characterized in that: The amount of the water-soluble polymer material added in the prescription ranges from 5wt.% to 40wt.%; the amount of the water-soluble high glass transition temperature material added in the prescription ranges from 3wt.% to 70wt.%, preferably from 5wt.% to 40wt.%.

5. The method according to claim 1, characterized in that The water-soluble drugs are ciprofloxacin hydrochloride, tobramycin sulfate, amikacin sulfate, salbutamol sulfate, terbutaline sulfate, isoniazid, colistin sulfate, pyrazinamide, kanamycin sulfate, roflumilast, octreotide acetate, netilmicin sulfate, disodium cromoglycate, amphotericin B, ipratropium bromide, glycopyrrolate, exenatide, semaglutide, liraglutide, insulin (acidic conditions), acetylcysteine, ribavirin, zanamivir, salbutamol hydrochloride, and aclidinium bromide.

6. The method according to claim 1, characterized in that The spray drying process has an inlet temperature range of 100-150° C., a feed rate range of 0.3-30 mL / min, and an air intake rate range of 246-742 L / h.

7. The method according to claim 1, characterized in that The method comprises the following steps: a. Add the water-soluble polymer material or the water-soluble high glass transition temperature material into distilled water and stir magnetically at room temperature until it is completely dissolved; b. adding the water-soluble pharmaceutically active substance to the solution obtained in step a, stirring magnetically at room temperature until completely dissolved to obtain a feed solution for spray drying; c. After the mixed solution in step b is stirred evenly, it is spray dried to obtain drug-loaded particles of the corresponding pharmaceutically active substance. The spray drying process is controlled in the inlet temperature range of 100-150°C, the feed rate range of 0.3-30mL / min, and the air intake rate range of 246-742L / h.

8. The particles for large-dose water-soluble drug inhalation powder prepared by the method according to any one of claims 1 to 7, characterized in that: The surface of the particles is coated with a layer of polymer coating film, and the polymer coating film formed on the surface of the particles after the pharmaceutically active substance is absorbed is composed of a water-soluble polymer material.

9. The particles for large-dose water-soluble drug inhalation powder prepared by the method according to any one of claims 1 to 7, characterized in that: The particles use a high glass transition temperature material as a glass matrix, and the pharmaceutically active substance is uniformly dispersed in the glass matrix.

10. The particle according to claim 8 or 9, characterized in that The inhalation powder particles are nearly spherical, with an aerodynamic particle size ranging from 0.5 to 10 μm, preferably 1 to 5 μm.

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