CN117338756A

CN117338756A - Preparation method of aspirin dry powder inhalation preparation

Info

Publication number: CN117338756A
Application number: CN202311343536.9A
Authority: CN
Inventors: 董斌; 赵艳; 于颖; 赵梦伟; 向心雨; 张钰茏; 黄德春; 李涵涵; 朱煜钿
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2023-10-17
Filing date: 2023-10-17
Publication date: 2024-01-05

Abstract

The invention belongs to the technical field of preparation of pharmaceutical preparations, and in particular relates to a preparation method of an aspirin dry powder inhalation preparation. The carrier-free aspirin dry powder inhalant particles prepared by the invention can be administered through pulmonary inhalation, so that the first pass effect of the liver is avoided, and the irritation of aspirin to gastrointestinal tract is reduced.

Description

Preparation method of aspirin dry powder inhalation preparation

Technical Field

The invention belongs to the technical field of preparation of pharmaceutical preparations, and particularly relates to a preparation method of an aspirin dry powder inhalation preparation.

Background

Aspirin, also known as acetylsalicylic acid, has a CAS number of 50-78-2. Is prepared from salicylic acid and acetic anhydride through acetylation reaction. Aspirin has a melting point of 136-140 deg.C, a boiling point of 321.4 deg.C, is usually white needle-like or plate-like crystals, is slightly soluble in water, is soluble in organic solvents such as ethanol, acetone, diethyl ether, chloroform, etc., and is also soluble in alkaline solutions, but is decomposed at the same time. The traditional nonsteroidal anti-inflammatory drug is used for relieving fever and pain, is widely used for treating pain, fever and inflammation, has antithrombotic effect in vivo, can inhibit the release reaction of platelets and platelet aggregation, is the most widely used anti-platelet aggregation drug, and is clinically used for preventing and treating angina, myocardial infarction, cerebral thrombosis and the like.

Although aspirin has various excellent activities and medicinal effects, aspirin not only has a sour taste, but also stimulates the gastrointestinal tract to induce gastric ulcer or duodenal ulcer. The main mechanisms of aspirin causing gastrointestinal damage include (a) inhibition of platelet aggregation resulting in impaired hemostatic function; (b) Inhibiting cyclooxygenase (COX-1), reducing Prostaglandin (PG) production, increasing gastrointestinal mucosal blood flow, stimulating mucous secretion and promoting epithelial cell proliferation, aspirin weakens the protective effect of prostaglandin on gastrointestinal tract, and makes it more vulnerable to conventional risk factors (such as acid, digestive enzymes and bile salts); (c) Physically breaking the protective phospholipid barrier of the stomach, creating an environment that is prone to ulcer formation. On the other hand, for acetylsalicylic acid molecules such as aspirin, the use of liquid forms is not recommended because the drug will hydrolyze upon exposure to an aqueous environment.

Pulmonary inhalation administration refers to the delivery of drugs directly to the lungs to induce local or systemic therapeutic effects, the principle of which is: the target drug is formulated as aerosol particles or dry powder particles and then inhaled actively or passively by the patient into the airways and lungs. Pulmonary inhalation administration has the following advantages over other routes of administration: (a) The effect is direct, and the inhalation mode is compared with the conventional oral administration, the medicinal powder can be more directly contacted with target organs and tissues (trachea and lungs); (b) The medicine has the advantages of quick effect, large pulmonary absorption area, thin alveolar epithelial cell membrane, high permeability and quick absorption, and can take 3-5 minutes at the highest effect after the quick-acting beta 2 receptor inhalant formoterol enters the body; (c) The dosage of the medicine is small, the absorption efficiency of the alveolar medicine is higher, the single-dose bulk drug API content in most inhalants is in the order of mg or 10mg, and the tablet API dosage is in the order of 10mg or 100 mg; (d) The adverse reaction is small, the first pass effect of the liver is avoided, and the adverse reaction of the gastrointestinal tract is reduced; the dosage of the API entering the systemic circulation is much smaller than that of the conventional oral administration, so that hormone absorption in the medicine is reduced; (e) Local/systemic effect, pulmonary delivery can be achieved not only for the delivery of small molecule drugs for the treatment of local diseases such as asthma or COPD, but also for the delivery of macromolecular drugs such as insulin, vaccines, etc. for the treatment of systemic diseases. Thus, pulmonary inhalation has become an alternative to injection, enabling non-invasive administration, while achieving dose reduction and increased bioavailability.

Inhalation formulations mainly include four pharmaceutical formulations of inhalation liquid formulations, inhalation sprays, inhalation aerosols and inhalation powder aerosols, i.e. dry powder inhalants (Dry Powder Inhalers, DPIs). Wherein DPIs are novel inhalation formulation dosage forms combining powder science and particle engineering, micronized drugs are stored in capsules, vesicles or reservoirs, alone or mixed with carriers, and are taken by patientsDynamic inhalation, the medicine is atomized and dispersed by a special inhalation device, and then enters the lung along with the airflow. Compared with inhalation liquid preparations, inhalation sprays and inhalation aerosols, DPIs have the following characteristics: 1) The use is convenient, and the patient compliance is good; 2) No propellant exists, so that environmental pollution is avoided; 3) The dosage of the drug is accurate; 4) The composition does not contain solvents such as preservative, ethanol and the like, and has no irritation to mucous membranes and lungs; 5) The medicine is solid and has good stability. In order to make the pulmonary deposition efficiency of dry powder inhalants higher, there is a more stringent requirement on the drug particle size of micronized drugs, and for inhaled particles, most insoluble particles with a diameter greater than 5 μm are deposited on the upper respiratory tract or main bronchi, have a high viscosity, and exhibit poor inhalation performance and flow rate. The particle size distribution of the particles suitable for pulmonary delivery of the drug is generally recognized to be between 1 and 5 μm, with smaller particle sizes providing greater overall drug pulmonary deposition, peripheral bronchial deposition and absorption rates, and vice versa. Therefore, the particle size of the inhalable formulation must be in the range of 1 μm to 5 μm to achieve efficient deep lung delivery ^] . Soon after inhalation, particles smaller than 1 μm will exhale, while particles larger than 5 μm will deposit in large conductive airways and oropharyngeal areas. Therefore, controlling particle size is critical to developing an effective pulmonary delivery system.

At present, the aspirin available in the market mainly comprises common tablet, enteric coated capsule, effervescent tablet, suppository and other dosage forms, and the dry powder inhalation dosage form is not available temporarily, so that the development and preparation of the aspirin dry powder inhalation preparation without adding any auxiliary materials are necessary to make up the market vacancy. As described above, dry powder inhalation formulations can meet the demands for stability and penetration into the lungs, reduce the irritation of aspirin to the gastrointestinal tract, improve patient compliance, and reduce the dosage used and improve bioavailability. The particle size of the aspirin crystals in most of the current researches is mainly distributed in hundred micrometers, for example, an aspirin crystal provided in patent document with publication number of CN 110156602A, while the aspirin particles smaller than 5 μm are added with polyethylene glycol and other auxiliary materials, so that polyethylene glycol is not approved by FDA for dry powder inhalation preparations at present, and potential toxicity and safety of the dry powder inhalation preparations can be not confirmed. Most new drug delivery systems use a variety of excipients and polymeric materials, but they may introduce additional costs, risks of formulation safety and instability, and studies of safety and stability remain to be improved. The total dosage of single inhalation is limited, and excessive dosage can cause discomfort of patients, the single total dosage can be improved by adopting carrier-free DPIs, the complexity of the preparation is reduced, and adverse reactions possibly caused by some auxiliary materials are avoided, so that the development of an aspirin dry powder inhalation preparation without adding the auxiliary materials is necessary.

Disclosure of Invention

The invention aims to: the invention aims to provide a novel aspirin crystallization and granulation process, which is used for preparing stable carrier-free aspirin particles with narrow particle size distribution and applying the carrier-free aspirin particles to dry powder inhalation preparations. Specifically, the invention utilizes multistage vortex reaction equipment to carry out turbulence reinforced anti-solvent crystallization and combines a spray freeze drying method, and aspirin dry powder inhalation particles with uniform particle size distribution, good particle morphology and stable chemical property can be prepared without other carriers and auxiliary materials. The carrier-free aspirin dry powder inhalant particles prepared by the invention can be administered through pulmonary inhalation, so that the first pass effect of the liver is avoided, and the irritation of aspirin to gastrointestinal tract is reduced.

The technical scheme is as follows: the aim of the invention is achieved by the following technical scheme: the invention provides a preparation method of a dry powder inhalation preparation granule of non-carrier aspirin, which adopts a multistage vortex reaction device and combines a spray freeze drying method to prepare the dry powder inhalation granule of non-carrier aspirin. The invention discloses a multistage vortex enhanced reaction device disclosed by an inventor in CN115999494A, which comprises two first-stage reaction devices and two second-stage reaction devices, wherein each reaction device is provided with a mixing reaction cavity, the inner wall of the mixing reaction cavity is provided with an annular guide wall which is annular and has radian, the annular guide wall is provided with two inlets, the initial velocity direction of fluid entering the mixing reaction cavity from the inlets is the tangential direction of the annular guide wall, and the two fluids can be mixed and reacted in the mixing reaction cavity.

The invention provides a preparation method of an aspirin carrier-free dry powder inhalation preparation by adopting the two-stage vortex reinforced reaction device. By using the two-stage vortex reinforced reaction device, the two reaction fluids, namely, the flow rate ratio of two-phase liquid, are arranged to collide to generate high-shear turbulence, so that the contact and mass transfer of the two reaction fluids under the conditions of high dispersion, high turbulence, strong mixing and rapid interface update are realized, the liquid-liquid is subjected to micro-mixing, micro-nano particles are prepared at high efficiency, and the dry powder preparation particles of inhalable aspirin, which have stable structure, small particle size and narrow particle size distribution range, are prepared.

The preparation method of the aspirin dry powder inhalation preparation specifically comprises the following steps:

the method comprises the steps of adding raw material medicine aspirin into absolute ethyl alcohol to be dissolved to obtain an aspirin ethanol solution with the minimum concentration of 10mg/mL, namely, the concentration of the aspirin in the aspirin ethanol solution is between 10mg/mL and a saturated solution, and the concentration of the saturated solution of the aspirin ethanol solution is 142mg/mL;

pure water with the volume of 10-20 times of that of the aspirin ethanol solution is prepared, pure water is divided into two equal parts to be used as two materials, the same aspirin ethanol solution is divided into two equal parts to be used as two other materials, the four materials are respectively conveyed and injected into four inlets of the two-stage vortex enhanced reaction device, the four inlets of the two-stage vortex enhanced reaction device are the inlet ends of two first-stage reaction devices in the two-stage vortex enhanced reaction device, the first inlet end and the second inlet end are two inlets of one first-stage reaction device, the third inlet end and the fourth inlet end are two inlets of the other first-stage reaction device, the four inlets are respectively connected with a peristaltic pump through silica gel tubes, the other ends of the two peristaltic pumps connected with the first inlet end and the third inlet end are communicated with the aspirin ethanol solution, correspondingly, the other ends of the other two peristaltic pumps connected with the second inlet end and the fourth inlet end are communicated with pure water, wherein one strand of aspirin ethanol solution and one strand of pure water are conveyed and injected into two inlets of the same first-stage reaction device through the peristaltic pumps according to the rotation speed ratio of 5:100-10:100, the other strand of aspirin ethanol solution and one strand of pure water are simultaneously conveyed and injected into two inlets of the other first-stage reaction device according to the same rotation speed ratio, materials mixed in the first-stage reaction device are further mixed through the second-stage reaction device and then flow out through an outlet of the second-stage reaction device, the outlet of the second-stage reaction device is an outlet of the two-stage vortex enhanced reaction device, and suspension can be collected at the outlet of the two-stage vortex enhanced reaction device under the ice bath environment;

spraying the suspension into liquid nitrogen through a spray freezer, transferring into a freeze dryer for freeze drying, and setting the temperature of the freeze drying at-17 ℃ for 6-48 hours, preferably 24 hours to obtain the aspirin dry powder inhalation preparation.

The liquid inlet speed corresponding to the peristaltic pump is that the liquid inlet speed is equal to 27.5mL/min per 100rmp of the peristaltic pump.

As a preferred embodiment of the preparation method of the dry aspirin powder inhalation preparation, the concentration of the aspirin alcohol solution is 142mg/mL, and the aspirin alcohol solution and the pure water are delivered and injected into two inlets of the same primary reaction device through peristaltic pumps according to the rotation speed ratio of 10:100.

As a preferred embodiment of the preparation method of the dry aspirin powder inhalation preparation, the concentration of the aspirin alcohol solution is 110mg/mL, and the aspirin alcohol solution and the pure water are delivered and injected into two inlets of the same primary reaction device through peristaltic pumps according to the rotation speed ratio of 5:100.

Preferably, the spraying liquid inlet speed is 6-30 mL/min.

Preferably, the spraying pressure is 0.03Mpa to 0.3Mpa.

The technical effects are as follows:

through implementation of the technical scheme, the invention prepares the dry powder meeting the requirement of dry powder absorption in a two-stage vortex reinforced reaction device by combining a turbulence reinforced antisolvent crystallization method with a spray freeze drying methodAspirin particles with particle diameter d ₅₀ The particle size distribution is 1-5 μm, and the particle size distribution is narrower, and can be used as dry powder inhalation preparation.

Compared with the dry powder inhalation preparation prepared only by a turbulence reinforced anti-solvent crystallization method, the particle size d of the dry powder inhalation preparation of aspirin, which is obtained by the preparation method ₅₀ The particle size of the aspirin dry powder inhalation preparation is smaller than 5 mu m, the particle size is small, the total deposition of the lung, the deposition of the peripheral bronchus and the absorption rate of the medicine are high, and the particle size of the aspirin dry powder inhalation preparation obtained by the preparation method provided by the invention has been proved to have certain storage chemical property stability and atomization performance stability through tests.

Drawings

FIG. 1 is a schematic diagram showing the connection of devices used in the preparation process in the example, wherein 1 and 7 represent a container of an ethanol solution containing aspirin, 2 represent peristaltic pumps, 5 represent a container of a product suspension, 3 and 4 represent a container of pure water, 6 represent a two-stage vortex enhanced reaction apparatus, 8 represent a first inlet port, 9 represent a second inlet port, 10 represent a third inlet port, and 11 represent a fourth inlet port;

FIG. 2 is an SEM image of dry aspirin powder as a product prepared in examples 1-4;

FIG. 3 is a graph showing the effect of the forward/reverse solvent ratio and drying mode on particle size distribution;

FIG. 4 is a graph showing the effect of drug concentration on particle size distribution;

FIG. 5 is a graph showing the effect of spray pressure on particle size distribution during spray freeze drying;

FIG. 6 is a graph showing the effect of liquid feed rate on particle size distribution during spray freeze drying;

fig. 7 is a FTIR spectrum of the drug substance and the dry powder aspirin product prepared in examples 1-4.

Detailed Description

The reaction system for preparing the aspirin suspension in the following examples and comparative example 1 is schematically shown in fig. 1, the apparatus for preparing the aspirin suspension comprises four peristaltic pumps and a multistage vortex-enhanced reaction apparatus as disclosed in CN115999494a, specifically a two-stage vortex-enhanced reaction apparatus is adopted, the apparatus comprises two first-stage reaction apparatuses and one second-stage reaction apparatus, four inlet ends on the two-stage vortex-enhanced reaction apparatus are inlet ends of the two-stage reaction apparatus, a first inlet end 8 and a second inlet end 9 are two inlets of one-stage reaction apparatus, a third inlet end 10 and a fourth inlet end 11 are two inlets of the other-side first-stage reaction apparatus, four peristaltic pumps are connected through a silicone tube, the other ends of the two peristaltic pumps connected with the first inlet end 8 and the third inlet end 10 are ethanol solutions of aspirin, the other ends of the other two peristaltic pumps connected with the second inlet end 9 and the fourth inlet end 11 are pure water, namely 1 and 7 represent containers for the ethanol solutions containing aspirin, 3 and 4 represent containers for the pure water, and the whole apparatus 6 is immersed in a silica gel bath tube with an inner diameter of 2 mm. The container 1 of the ethanol solution containing aspirin on the left side and the container 4 containing pure water are taken as a group to convey the content liquid into the two-stage vortex reactor through a peristaltic pump to perform a premixing reaction, and meanwhile, the container 3 of the ethanol solution containing aspirin on the right side and the container 7 containing pure water are taken as a group to convey the content liquid into the two-stage vortex reactor through a peristaltic pump to perform a premixing reaction; two reaction liquids respectively formed by the premixing reaction at the two sides enter a secondary vortex reaction device to carry out final mixing reaction, thus obtaining uniform suspension 5.

The reaction system is assembled, and aspirin dry powder products with different particle sizes are obtained by setting different reaction conditions, wherein the specific reaction conditions are shown in the following examples and comparative examples. The aspirin crude drug is purchased from Shandong Xinhua pharmaceutical Co., ltd, and the content is 99%.

Example 1

Step one, an ethanol saturated solution of aspirin was prepared by adding 2.84g of aspirin to 20mL of ethanol at room temperature of 25℃and dissolving the aspirin in an ethanol saturated solution at a concentration of about 142mg/mL.

And secondly, respectively filling 10mL of ethanol saturated solution of aspirin with two clean beakers, filling 100mL of pure water with the two clean beakers, setting the rotating speed of a peristaltic pump, wherein the rotating speed of the peristaltic pump for the aspirin is 10rmp, the rotating speed of the peristaltic pump for each 100rmp is equal to the feeding speed of 27.5mL/min, keeping the temperature in the reactor at 25 ℃ when the reactor is full of the solution, and starting to collect suspension when white crystal particles flow out.

And thirdly, immediately performing spray freeze drying on the collected suspension (the concentration is approximately equal to 12.90 mg/mL), namely spraying the suspension into 400mL of liquid nitrogen under the conditions of 0.03Mpa and 50rmp approximately equal to 30mL/min of feeding speed, and performing freeze drying for 24 hours at the temperature of minus 17 ℃ to obtain the final product, namely the aspirin dry powder.

The particle size and morphology of the obtained aspirin dry powder are characterized by using a particle size meter and a scanning electron microscope, and the experiment is repeated for three times, and the result shows that the average particle size d of the obtained product ₅₀ 4.34.+ -. 0.37. Mu.m.

Example 2

And secondly, filling 10mL of ethanol saturated solution of aspirin with two clean beakers, filling 200mL of pure water with the two clean beakers, setting the rotating speed of a peristaltic pump, wherein the rotating speed of the peristaltic pump is 27.5mL/min when the ethanol solution of aspirin is 5rmp and the pure water is 100 rmp. When the reactor was filled with the solution, the temperature in the reactor was kept at 25 ℃, and the suspension was collected when white crystalline particles were allowed to flow out.

And thirdly, immediately carrying out spray freeze drying on the collected suspension (with the concentration of approximately equal to 6.76 mg/mL) to obtain the final product, namely the dry aspirin powder, wherein the spray freeze drying is carried out on the collected suspension (with the concentration of approximately equal to 12.90 mg/mL) under the conditions that the pressure is 0.03Mpa and the feeding speed is 50rmp approximately equal to 30mL/min, namely, the spray drying is carried out on the collected suspension in 800mL of liquid nitrogen, and the freeze drying is carried out for 24 hours at the temperature of minus 17 ℃.

The particle size and morphology of the obtained aspirin dry powder are characterized by using a particle size meter and a scanning electron microscope, and the experiment is repeated for three times, and the result shows that the average particle size d of the obtained product ₅₀ 4.41.+ -. 0.43 μm.

Example 3

Step one, an aspirin ethanol solution having a concentration of 110mg/mL was prepared by adding 2.2g of aspirin to 20mL of ethanol at room temperature (25 ℃).

And secondly, respectively filling 10mL of aspirin ethanol solution in two clean beakers, filling 100mL of pure water in the two clean beakers, setting the rotating speed of a peristaltic pump, wherein the rotating speed of the peristaltic pump is 27.5mL/min, and the rotating speed of the peristaltic pump is 10rmp and the rotating speed of the pure water is 100 rmp. When the solution is filled in the kettle type reactor, the temperature in the reactor is kept at 25 ℃, and the suspension is collected when white crystal particles flow out.

And thirdly, immediately performing spray freeze drying on the collected suspension (the concentration is approximately equal to 10.00 mg/mL), namely spraying the suspension into 400mL of liquid nitrogen under the conditions of 0.03Mpa and 50rmp approximately equal to 30mL/min of feeding speed, and performing freeze drying for 24 hours at the temperature of minus 17 ℃ to obtain the final product, namely the aspirin dry powder.

The particle size and morphology of the obtained aspirin dry powder are characterized by using a particle size meter and a scanning electron microscope, and the experiment is repeated for three times, and the result shows that the average particle size d of the obtained product ₅₀ 4.86.+ -. 0.49. Mu.m.

Example 4

And secondly, respectively filling 10mL of aspirin ethanol solution in two clean beakers, filling 200mL of pure water in the two clean beakers, setting the rotating speed of a peristaltic pump, wherein the rotating speed of the peristaltic pump is 27.5mL/min, and the rotating speed of the peristaltic pump is 100rmp when the ethanol solution of aspirin is 5 rmp. The temperature in the reactor was kept at 25℃and suspension was collected when the solution was filled in the tank reactor and white crystalline particles were tapped at the outlet.

And thirdly, immediately performing spray freeze drying on the collected suspension (the concentration is approximately equal to 5.24 mg/mL), namely spraying the suspension into 800mL of liquid nitrogen under the conditions of 0.03Mpa and 50rmp approximately equal to 30mL/min of feeding speed, and performing freeze drying for 24 hours at the temperature of minus 17 ℃ to obtain the final product, namely the aspirin dry powder.

The particle size and morphology of the obtained aspirin dry powder are characterized by using a dry powder particle sizer and a scanning electron microscope, and the experiment is repeated for three times, and the result shows that the average particle size d of the obtained product ₅₀ 4.53.+ -. 0.56 μm.

Fig. 2 is a photograph showing the morphology characterization of the product particles prepared in examples 1 to 4 by using a scanning electron microscope.

Example 5

Example 5 differs from example 1 only in that the drug concentration in step one is 100mg/mL, the rest of the operations being identical;

example 6

Example 6 differs from example 1 only in that the drug concentration in step one is 120mg/mL, the rest of the procedure being identical;

example 7

Example 7 differs from example 1 only in that the drug concentration in step one is 130mg/mL, the rest of the operations being identical;

examples 8 to 12

Examples 8 to 12 differ from example 1 only in that the spray pressures in step three were 0.06Mpa, 0.09Mpa, 0.1Mpa, 0.2Mpa, 0.3Mpa, respectively, and the rest of the operations were identical;

examples 13 to 17

Examples 13 to 17 differ from example 1 only in that the liquid feed rates in step three were 6mL/min, 12mL/min, 18mL/min, and 24mL/min, respectively, with the remaining operations being identical;

comparative example 1

Comparative example 1 differs from example 1 only in that the concentration of the drug solution in the first step, i.e., the aspirin ethanol solution, was 90mg/mL, and the remaining operations were identical;

comparative example 2

Comparative example 2 differs from example 1 only in that in step three of this comparative example 2, the suspension is directly subjected to a drying treatment under the following conditions: freeze-drying in a freeze dryer at-17deg.C for 48 hr to obtain the final product.

Comparative example 3

Comparative example 3 differs from example 2 only in that step three of this comparative example 3 is to directly subject the suspension to a drying treatment under the following conditions: freeze-drying in a freeze dryer at-17deg.C for 48 hr to obtain the final product.

Particle size test

The particle size of the dry aspirin powder prepared in all examples and comparative examples was measured dry using a laser particle size analyzer at a dispersion pressure of 2.0bar, 3 times per parallel;

as shown in FIG. 3, the particle diameters d of the aspirin particles prepared in example 1, example 2, comparative example 2, and comparative example 3 ₅₀ Comparing the distribution, it can be seen from the comparison of example 1 and example 2 that the ratio of the liquid medicine to water is changed during the preparation process, and the particle diameter d of the aspirin particles is correspondingly prepared ₅₀ The distribution change is not obvious, and the particle diameter d of the prepared aspirin particle ₅₀ Are all smaller than 5 mu m; from a comparison of example 1 and comparative example 2, or a comparison of example 2 and comparative example 3, it can be seen that if the turbulent-flow-enhanced antisolvent crystallization treatment is followed by direct freeze-drying treatment, the particle size d is obtained ₅₀ Larger than 10 μm, and larger particle size does not meet the condition of dry powder inhalation.

As shown in FIG. 4, the particle diameters d of the aspirin particles prepared in example 1, example 4, example 5, example 6, example 7, and comparative example 1 were as follows ₅₀ Comparing the distribution, it can be seen that the particle diameter d of the aspirin particles can be adjusted by changing the concentration of the drug in the first step ₅₀ Distribution, and particle size d of aspirin particles prepared as comparative example 1 ₅₀ The distribution shows that if the concentration of the liquid medicine is too low, d is prepared ₅₀ Will be greater than 5 μm and will have a slight tendency to decrease in particle size with increasing drug concentration, but will have particle size d in the range of drug concentration from 100mg/mL to saturated solution (142 mg/mL) ₅₀ Are all below 5 μm.

As shown in FIG. 5, examples 1, 8 to 12 are prepared to give aspartameGrain diameter d of forest granule ₅₀ Comparing the distribution, it can be seen that if the spray pressure is changed during spray freeze drying treatment in the preparation process, the particle diameter d of the aspirin particles is correspondingly prepared ₅₀ The distribution change is not obvious, and the particle diameter d of the prepared aspirin particle ₅₀ Are all smaller than 5 mu m;

as shown in FIG. 6, the particle diameters d of the aspirin particles prepared in example 1, example 13 to example 17 are shown ₅₀ Comparing the distribution, it can be seen that if the liquid inlet rate in the spray freeze drying treatment process is changed in the preparation process, the particle diameter d of the aspirin particles is correspondingly prepared ₅₀ The distribution change is not obvious, and the particle diameter d of the prepared aspirin particle ₅₀ Are all smaller than 5 mu m;

fourier transform infrared spectrum testing

As shown in FIG. 7, which shows the Fourier transform infrared spectra of the crude drug and the dry aspirin powder prepared in examples 1-4, wherein the API represents the crude drug, DPI-1, DPI-2, DPI-3 and DPI-4 represent the dry aspirin powder prepared in examples 1-4 in sequence, the chemical structure of the aspirin is not changed in the preparation process, and the chemical property of the dry aspirin powder obtained by the preparation method is stable.

Atomization performance measurement

The dry powder of aspirin prepared in examples 1 to 4 was filled into No. 3 HPMC capsules (10.+ -. 0.5 mg/granule) to obtain an aspirin inhalation powder aerosol, and the Emission Fraction (EF), in vitro drug deposition rate (Fine Particle Fraction, FPF) and mass median aerodynamic diameter MMAD (Mass MedianAerodynamic Diameter) of the inhalation powder aerosol were measured using a new generation pharmaceutical impactor (Next Generation Impactor, NGI).

Specific test procedure of Emission Fraction (EF): and (3) filling the aspirin dry powder into No. 3 HPMC capsules (20+/-0.5 mg/granule) to obtain the aspirin inhalation powder spray, and measuring the emission dosage of the inhalation powder spray by adopting a new generation of medicinal impactors (Next Generation Impactor, NGI). EF refers to the percentage of the total drug amount that leaves the inhaler.

Specific test procedure for in vitro drug deposition rate (Fine Particle Fraction, FPF): and (3) filling the aspirin dry powder into No. 3 HPMC capsules (10+/-0.5 mg/granule) to obtain the aspirin inhalation powder spray, and measuring the in-vitro medicine deposition rate of the inhalation powder spray by adopting a new generation of medicinal impactors (Next Generation Impactor, NGI). FPF is the most intuitive parameter for evaluating the delivery efficiency of the inhaled powder aerosol pulmonary drug, reflects the delivery capacity of the drug to the lung, and refers to the percentage of the mass of the drug deposited in the lung to the total mass of the drug collected, namely the percentage of the drug deposited in the lung to the total drug released from the device, and the larger the FPF, the more favorable the pulmonary drug delivery. Specifically, the FPF is equal to the amount of medication received by the five collection trays S2 through S7 divided by the total amount of medication in the device. The FPF is mainly related to the particle size distribution of particles in the powder aerosol, and the shape, density, fluidity, hygroscopicity, uniformity and the like of the particles have a certain influence on the particles.

(1) EF = total recovered mass from throat to grade 7/total drug amount ×100%

(2) FPF = sum of recovered mass from stage 2 to stage 7/total mass of drug delivered × 100%

TABLE 1 influence of different concentrations of Aspirin ethanol solutions and different feed-to-liquid ratios on the atomization performance of Aspirin dry powders

The atomization performance of the powder is evaluated by utilizing NGI, and the FPF (Fine Particle Fraction ) meets the requirement that the lung deposition rate of the powder aerosol specified in Chinese pharmacopoeia 2015 is more than 10 percent; and the median mass aerodynamic particle size MMAD is between 1 and 5 mu m, and the result shows that the obtained aspirin dry powder preparation has better atomization performance. The aspirin dry powder inhalant disclosed by the invention is simple in preparation method and process, does not contain any auxiliary materials or preservative in the preparation process, does not introduce other impurities in the production process, has good reproducibility, can be produced in a large scale, automatically and continuously, and is easy to realize industrial production.

The invention is not a matter of the known technology.

The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims

1. A method for preparing an aspirin dry powder inhalation preparation, which is characterized by comprising the following steps: the raw material medicine aspirin is added into absolute ethyl alcohol to be dissolved, so as to obtain an aspirin ethanol solution with the concentration range of 10 mg/mL-saturated; pure water with the volume of 10-20 times of that of the aspirin ethanol solution is prepared, pure water is divided into two equal parts to be used as two materials, the aspirin ethanol solution is also divided into two equal parts to be used as another two materials, four materials are respectively conveyed and injected into four inlets of a two-stage vortex enhanced reaction device, the four inlets of the two-stage vortex enhanced reaction device are the inlet ends of two first-stage reaction devices in the two-stage vortex enhanced reaction device, the first inlet end and the second inlet end are the two inlets of one first-stage reaction device, the third inlet end and the fourth inlet end are the two inlets of the other first-stage reaction device, the four inlets are respectively connected with a peristaltic pump through a silica gel tube, the other ends of the two peristaltic pumps connected with the first inlet end and the third inlet end are communicated with the aspirin ethanol solution, correspondingly, the other ends of the other two peristaltic pumps connected with the second inlet end and the fourth inlet end are communicated with pure water, wherein one strand of aspirin ethanol solution and one strand of pure water are conveyed and injected into two inlets of the same first-stage reaction device through the peristaltic pumps according to the rotation speed ratio of 5:100-10:100, the other strand of aspirin ethanol solution and one strand of pure water are simultaneously conveyed and injected into two inlets of the other first-stage reaction device according to the same rotation speed ratio, materials mixed in the first-stage reaction device are further mixed through the second-stage reaction device and then flow out through an outlet of the second-stage reaction device, the whole vortex reaction is performed in an ice bath environment, and suspension can be collected at an outlet of the two-stage vortex reinforced reaction device; spraying the suspension into liquid nitrogen through a spray freezer, transferring into a freeze dryer for freeze drying, and setting the temperature of freeze drying at-17 ℃ for 6-48 hours to obtain the aspirin dry powder inhalation preparation.

2. The method for preparing an aspirin dry powder inhalation formulation according to claim 1, wherein the time of freeze-drying is 24 hours.

3. The method for preparing an aspirin dry powder inhalation formulation according to claim 1, wherein the concentration of the aspirin ethanol solution is 142mg/mL, and the aspirin ethanol solution and the purified water are fed through peristaltic pumps at a speed ratio of 10:100 to two inlets of the same primary reaction device.

4. The method for preparing an aspirin dry powder inhalation formulation according to claim 1, wherein the concentration of the aspirin ethanol solution is 110mg/mL, and the aspirin ethanol solution and the purified water are fed through peristaltic pumps at a speed ratio of 5:100 to two inlets of the same primary reaction device.

5. The method for preparing an aspirin dry powder inhalation formulation according to claim 1, wherein the spray liquid inlet speed is 6-30 mL/min.

6. The method for preparing an aspirin dry powder inhalation preparation according to claim 1, wherein the spraying pressure is 0.03Mpa to 0.3Mpa.

7. The method for preparing an aspirin dry powder inhalation formulation according to claim 1, wherein the spraying pressure is 0.1Mpa.