Inhalation drug delivery device and design method

Abstract

The invention discloses an inhalation administration device and a design method, and mainly relates to the technical field of medical instruments. The device comprises a capsule base, a capsule body, a capsule cabin and a suction nozzle, an inner cavity of the suction nozzle is of an inverted trapezoid structure, and in other words, the diameter of the section is increased by 0.033 mm every time the inner area of the suction nozzle is raised by 1 mm from the bottom end to the top end. According to the design, by optimizing the internal flow field of the suction nozzle, the dispersity of medicine particles can be remarkably improved, wall surface deposition is reduced, and therefore the dispersity of the medicine particles and the lung deposition efficiency are improved. The invention also provides a design method based on lattice Boltzmann method-immersion boundary method-large eddy simulation multi-physics field coupling numerical simulation, and by setting specific performance evaluation parameters, the structure optimization of the inverted trapezoidal suction nozzle can be efficiently and accurately guided. An in-vitro deposition test shows that the performance of the device is superior to or equivalent to that of a commercially available product.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, and more particularly to an inhalation administration device and a design method. BACKGROUND

[0002] Inhalation administration is to atomize and disperse a specific drug into an aerosol form through a drug delivery device, and deliver the drug to the lungs through active or passive inhalation of a patient, so as to achieve the treatment of local or systemic diseases. It has been used for the treatment of respiratory system related diseases such as asthma, chronic obstructive pulmonary disease, and pneumonia. During inhalation, although the delivery efficiency of the drug will be affected by different inhalation administration methods, types of drug delivery devices, physicochemical properties of the drug, airway structure of the patient, and patient compliance, etc., the inhalation administration device will directly affect the delivery dose of the drug and the particle size distribution of the drug particles, thereby affecting the deposition mechanism, deposition mode and delivery efficiency of the drug particles in the respiratory tract. Therefore, the inhalation administration device is one of the main factors affecting the efficacy of inhalation administration.

[0003] Therefore, how to provide a design method of an inhalation administration device capable of improving the lung deposition efficiency and design the device is a problem to be solved by those skilled in the art. SUMMARY

[0004] In view of the above problems, the present application is proposed in order to provide an inhalation administration device and a design method which overcome the above problems or at least partially solve the above problems.

[0005] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions: The present application provides an inhalation administration device, which comprises a capsule seat, a suction nozzle, a capsule main body and a capsule cabin. The capsule seat is provided with a capsule cabin for accommodating the capsule main body and a puncture needle for piercing the capsule main body, and the two sides of the capsule seat are provided with air inlets. The suction nozzle is detachably connected to one end of the capsule seat, and the top end of the suction nozzle is in a wide-mouth structure.

[0006] Preferably, the suction nozzle is in an inverted ladder structure, and the diameter change rate of the internal region of the inverted ladder structure suction nozzle from the bottom end to the top end is 0.033 mm per 1 mm increase in section diameter.

[0007] Preferably, the inhalation administration device provided by the present application delivers inhalation powder.

[0008] Based on the above-mentioned inhalation administration device, a design method of an inhalation administration device is provided: S1: obtaining structure parameters of each part of the inhalation administration model, and establishing an initial inhalation administration model; S2: determining a calculation domain based on the initial inhalation administration model; S3: setting an inhalation drug particle flow value and an inhalation drug particle quantity value of an initial inhalation administration model; S4: performing inhalation administration simulation on the initial inhalation administration model according to the inhalation drug particle flow value and the inhalation drug particle quantity value, simulating an airflow field and drug particle motion of a calculation domain of the initial inhalation administration model by using a lattice Boltzmann method-immersed boundary method-large eddy simulation multi-physical coupling mechanism to obtain transient flow field data and drug particle motion data of the calculation domain; S5: establishing a dynamics model of the drug particles and the capsule in the calculation domain, and obtaining a resultant force on the drug particles in the calculation domain based on the dynamics model of the drug particles and the capsule; S6: setting at least one performance evaluation parameter, and evaluating the transient flow field data, the drug particle motion data and the resultant force of the calculation domain according to the performance evaluation parameter to obtain a performance evaluation result; S7: adjusting a structure parameter of the initial inhalation administration model based on the performance evaluation result until the performance evaluation result meets a preset performance index; S8: establishing an optimized inhalation administration model based on the structure parameter meeting the preset performance index.

[0009] Preferably, the calculation domain is a square cavity at a nozzle of the initial inhalation administration model and an internal region of the nozzle.

[0010] Preferably, the lattice Boltzmann method-immersed boundary method-large eddy simulation multi-physical coupling mechanism specifically comprises: simulating an airflow field of the calculation domain of the initial inhalation administration model by using the lattice Boltzmann method and the large eddy simulation method to obtain transient flow field data; a solving formula of the transient flow field is: ; in the formula, is a distribution function of a particle at a position , a time , and a discrete velocity direction , is a relaxation time, is an equilibrium state distribution function, is a volume force term, is a time change rate.

[0011] simulating drug particle motion of the initial inhalation administration model by using the immersed boundary method to obtain the drug particle motion data; an expression of the immersed boundary method is: ; in the formula, indicates a Dirac function.

[0012] The kinetic model formula of the medicine particles and the capsule is preferably: ; ; In the formula, , , , are the mass, the moment of inertia, the translational velocity and the angular velocity of the particles respectively; is the resultant force acting on the medicine particles, is the resultant moment.

[0013] The resultant force acting on the medicine particles is preferably including the fluid-structure coupling force , the gravity , the inter-particle force, the electrostatic attraction force and the centrifugal force .

[0014] The performance evaluation parameters preferably include the instantaneous angular velocity and the translational trajectory of the medicine particles, the percentage of the medicine particle mass in the prescription cavity at the outlet of the initial inhalation drug delivery model to the total emitted medicine particle mass, the residence time distribution and the spatial distribution of the medicine particles in the prescription cavity, and the transient flow velocity distribution of the calculation domain.

[0015] The above technical solution provided by the embodiment of the present application has at least the following beneficial effects: the internal geometry of the inhaler is optimized, and the dispersibility and the lung deposition efficiency of the medicine particles are significantly improved by combining the multi-physical field numerical simulation means. BRIEF DESCRIPTION OF DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor on the basis of the provided drawings.

[0017] Figure 1 is a structural schematic diagram of an inhalation drug delivery device provided in the embodiment of the present application; Figure 2 is a flow field and medicine particle distribution display diagram of an inhalation drug delivery device and an inhalation process provided in the embodiment of the present application; Figure 3 is a medicine particle dispersion display diagram provided in the embodiment of the present application; Figure 4 is a precise modeling schematic diagram of an existing experimental inhalation drug delivery device provided in the embodiment of the present application; Figure 5This is a design drawing of the inverted trapezoidal inhalation drug delivery device provided in an embodiment of the present invention; Figure 6 This is a schematic diagram of the inhalation drug delivery device model provided in an embodiment of the present invention; Figure 7 This is a physical illustration of the inhalation drug delivery device provided in an embodiment of the present invention.

[0018] Reference numerals: Capsule seat-1; Nozzle-2; Capsule body-3; Capsule compartment-4; Air inlet-5. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] This invention discloses a design method for an inhalation drug delivery device, which includes the following steps: S1: Obtain the structural parameters of each part of the inhalation drug delivery model and establish the initial inhalation drug delivery model; S2: Determine the computational domain based on the initial inhalation drug delivery model; S3: Set the inhalation flow rate and number of inhaled particles for the initial inhalation drug delivery model. S4: Based on the inhaled particle flow rate and the number of inhaled particles, the initial inhalation drug delivery model is simulated. The lattice Boltzmann method-immersion boundary method-large eddy simulation multi-physics coupling mechanism is used to simulate the airflow field and drug particle motion in the computational domain of the initial inhalation drug delivery model, and the transient flow field data and drug particle motion data in the computational domain are obtained. S5: Establish a dynamic model of drug particles and capsules in the computational domain, and obtain the resultant force on the drug particles in the computational domain based on the dynamic model of drug particles and capsules. S6: Set at least one performance evaluation parameter, evaluate transient flow field data, drug particle motion data and resultant force based on the performance evaluation parameter, and obtain the performance evaluation result; S7: Based on the performance evaluation results, adjust the structural parameters of the initial inhalation drug delivery model until the performance evaluation results meet the preset performance indicators; S8: Based on the structural parameters that meet the preset performance indicators, establish an optimized inhalation drug delivery model.

[0021] This invention provides an inhalation drug delivery device.

[0022] likeFigure 1 The device includes: a capsule seat 1, a suction nozzle 2, a capsule body 3, and a capsule chamber 4; The capsule seat 1 is provided with a capsule chamber 4 for accommodating the capsule body 3 and a puncture needle for piercing the capsule body. The lower middle part of the capsule seat 1 is provided with air inlets 5 on both sides. The suction nozzle 2 is detachably connected to one end of the capsule seat 1. The top of the suction nozzle 2 has a wide opening structure and the inner wall is flared in a beveled shape.

[0023] The inhalation drug delivery device is designed in an inverted trapezoidal shape, meaning the nozzle of the device is inverted trapezoidal. The rate of change from the bottom to the top of the internal region of the inverted trapezoidal nozzle 2 is such that for every 1 unit increase in height, the cross-sectional diameter increases by 0.033. Figure 5 As shown, three nozzle depths (a, b, and c) of 28mm, 33mm, and 38mm were provided for numerical calculation experiments, and the data comparison results are shown in Table 1.

[0024] Table 1. Comparison of Outlet Flow Rate Test Results between Inverted Trapezoidal and Standard Type Inhalation Drug Delivery Devices

[0025] The results show that the inverted trapezoidal inhalation drug delivery device is feasible. Both device values ​​a and c are greater than the standard values, indicating that the performance of the device of this invention is superior to or equivalent to commercially available products. Therefore, it is determined that the inverted trapezoidal design can meet the requirements for inhalation drug delivery.

[0026] This invention employs an innovative inverted trapezoidal nozzle structure and optimizes its diameter change rate, effectively improving the internal flow field distribution of the device. This structure slows down the airflow velocity and reduces turbulence intensity, thereby significantly improving the uniformity of drug particle dispersion and reducing collisions and deposition between particles and the nozzle's inner wall. The direct effect is increased lung deposition efficiency, allowing more drug to reach the target lesion area, providing users with a safer, more efficient, and convenient inhalation drug delivery solution.

[0027] This invention provides an embodiment of a design method for an inhalation drug delivery device, specifically including: Obtain the structural parameters of each part of the inhalation drug delivery model and establish an initial inhalation drug delivery model. 1) Structure Determination: Obtain structural drawings of the inhalation drug delivery device and determine the specific parameters of each component. Reconstruct the inhalation drug delivery device using these structural parameters, and obtain its accurate three-dimensional numerical model using Fortran.

[0028] 2) Computational Domain Extension: To study the initial dispersion of powder in the oral cavity, a simplified square cavity was connected to the mouthpiece of the inhalation drug delivery device to simulate the human oral cavity. This square cavity serves as the area for drug particle retention and mixing after the powder leaves the mouthpiece.

[0029] 3) Computational Mesh: The entire computational domain, including the square cavity at the nozzle of the initial inhalation drug delivery model and the internal region of the nozzle, is meshed. The immersion boundary method is used to ensure accurate fluid-structure interaction.

[0030] Set the inhalation flow rate and number of inhaled drug particles for the initial inhalation drug delivery model, and simulate inhalation drug delivery based on the inhalation flow rate and number of inhaled drug particles for the initial inhalation drug delivery model.

[0031] The negative pressure generated by the patient's inhalation was simulated, with transient output values ​​of 60 L / min, 90 L / min, and 120 L / min for the inhaled drug particles. A certain number of spherical drug particles, for example, 10,000 drug particles with a diameter distribution of 1-5 μm, were randomly placed inside the capsule body of the inhalation drug delivery device.

[0032] The airflow field and drug particle motion of the computational domain of the initial inhalation drug delivery model were simulated using a multi-physics coupling mechanism of lattice Boltzmann method-immersion boundary method-large eddy simulation, and transient flow field data and drug particle motion data of the computational domain were obtained.

[0033] The airflow field in the computational domain of the initial inhalation drug delivery model was simulated using the lattice Boltzmann method and large eddy simulation to obtain transient flow field data: The expression for the transient flow field is: ; In the formula, It is the position of the particle ,time Along the discrete velocity direction The distribution function, It's a relaxation time. It is the equilibrium distribution function. It is a volume force term. It is the rate of change over time.

[0034] The rotation and translation of the capsules, along with the movement of the powder particles, constitute a complex moving boundary problem. The immersed boundary method is employed to handle the interactions between these solid boundaries and the fluid. The solid moves independently within the computational domain, and its surface is represented by a set of Lagrange points.

[0035] At each time step, the fluid particle velocity information is transmitted to the solid boundary points via an interpolation function. Based on the no-slip boundary condition, the force required to match the fluid velocity with the solid boundary velocity is calculated. This force is fed back into the lattice Boltzmann method flow field solution via a distribution function. This yields the desired result, enabling accurate simulation of the influence of solid boundaries. Specifically, the immersion boundary method is used to simulate the movement of drug particles in the initial inhalation drug delivery model, obtaining drug particle movement data. The expression for the immersion boundary method is: ; In the formula, This represents the Dirac function, through which interpolation is performed.

[0036] A dynamic model of drug particles and capsules in the computational domain is established based on Newton's second law, and the resultant force on the drug particles in the computational domain is obtained based on the dynamic model of drug particles and capsules.

[0037] The kinetic model formula for drug particles and capsules is as follows: ; ; In the formula, , , , These are the particle's mass, moment of inertia, translational velocity, and angular velocity, respectively. It is the resultant force acting on the drug particles. It is the resultant torque.

[0038] The resultant force acting on the drug particles Including: fluid-structure interaction force ,gravity Interparticle forces and electrostatic attraction and centrifugal force .

[0039] Fluid-structure interaction The direct manifestation of the force exerted by a fluid on a solid, mainly including resistance and pressure gradient force; gravity : ; For powder quality acceleration due to gravity Interparticle forces: elastic collision forces Calculate collisions and friction between particles and between particles and walls; determine whether momentum exchange should be performed based on the distance between particles.

[0040] electrostatic attraction Considering the characteristic that drug particles are prone to static electricity, the attractive force between particles is calculated; K is a constant parameter that has been set through empirical adjustment.

[0041] Centrifugal force For powder rotating with the capsule inside the capsule chamber, the centrifugal force it experiences is mediated by the capsule's rotational angular velocity. Calculate the position r of the particle relative to the center of rotation: This force is one of the key driving forces that causes the powder to escape from the capsule. Figure 2 The flow field distribution during the inhalation process of the inhalation drug delivery device is shown.

[0042] like Figure 3 As shown, a specific moment is selected to demonstrate the flow field and drug powder distribution within the inhalation drug delivery device. The streamlines within the flow field begin at the air inlet of the nozzle and flow out at the nozzle. The movement of the powder is influenced by the flow field streamlines and eventually accumulates in the square cavity at the nozzle outlet. This square cavity is designed to simulate the human oral cavity, with the aim of studying the characteristics of the powder and its flow at the outlet.

[0043] Based on an existing specific implementation model BDD06, the numerical calculation model of the inhalation drug delivery device is further optimized. The corresponding product parameters and specific structure are as follows: Figure 4 As shown.

[0044] Multiple performance evaluation parameters are set, and the transient flow field data, drug particle motion data, and resultant forces in the computational domain are evaluated based on the performance evaluation parameters to obtain the performance evaluation results.

[0045] The performance evaluation parameters include: the instantaneous angular velocity and translational trajectory of the drug particles, the percentage of the mass of the drug particles in the outlet prescription cavity of the initial inhalation drug delivery model relative to the total mass of the emitted drug particles, the residence time distribution and spatial distribution of the drug particles in the prescription cavity, and the transient velocity distribution of the computational domain.

[0046] Based on the performance evaluation results, the structural parameters of the initial inhalation drug delivery model were adjusted until the performance evaluation results met the preset performance indicators.

[0047] The following is a detailed experimental procedure and output data provided in the embodiments of the present invention: Based on the optimized structural parameters that meet the preset performance indicators, an inverted trapezoidal inhalation drug delivery device was designed. A nozzle model was created using Solidworks 2022, saved as an STL file, and imported into the 3D printer's software for printing. The three views of the model are shown below. Figure 6 The three views of the actual object are shown in the figure. Figure 7 .

[0048] The inhalation drug delivery device provided by this invention is used to deliver inhaled powder, using peramivir powder as the inhaled drug particles. The deposition amount of each part of the peramivir powder is calculated using the new generation impactor detection device (NGI). The results are then input into NGI data analysis software to calculate the percentage of fine drug particles (FPF) and the median mass aerodynamic diameter (MMAD).

[0049] The specific experimental procedure is as follows: Weigh approximately 20 mg of peramivir powder and fill 10 capsules into the capsule chamber. Install all components of the NGI and check the system's airtightness. After confirming good airtightness, fix the inhalation flow rate and check the pressure stability. Once the pressure stability is good, set the inhalation time to 4 seconds and the delay time to 2 seconds, and sequentially insert 10 capsules into the mouthpiece for inhalation testing. After inhalation, rinse each part of the NGI with the mobile phase and collect the washings into different volumetric flasks, dilute to the mark, and calculate the amount of peramivir deposited in each part of the NGI. Use NGI data analysis software to calculate the percentage of fine drug particles (FPF) and the median mass aerodynamic diameter (MMAD).

[0050] Experimental results show that with the inverted trapezoidal inhalation device, the FPF of peramivir powder is 74.275% and the MMAD is 2.632 μm. The FPF of the inverted trapezoidal inhalation device is greater than the specified 10%, and the lung deposition rate meets the requirements. The inverted trapezoidal inhalation device studied in this invention has good drug particle delivery efficiency.

[0051] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on its differences from other embodiments. Similar or identical parts between embodiments can be referred to interchangeably. For the apparatus disclosed in the embodiments, since it corresponds to the method disclosed in the embodiments, the description is relatively simple; relevant parts can be referred to the method section.

[0052] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An inhalation drug delivery device, characterized in that, The device includes: a capsule seat (1), a suction nozzle (2), a capsule body (3), and a capsule compartment (4); The capsule seat (1) is provided with a capsule compartment (4) for accommodating the capsule body (3) and a puncture needle for piercing the capsule body (3). The capsule seat (1) is provided with air inlets (5) on both sides. The suction nozzle (2) is detachably connected to one end of the capsule seat (1), and the top of the suction nozzle (2) has a wide mouth structure.

2. The inhalation drug delivery device according to claim 1, characterized in that, The suction nozzle (2) has an inverted trapezoidal structure. The diameter of the inner region of the inverted trapezoidal suction nozzle (2) changes from the bottom to the top. For every 1 mm increase in height, the cross-sectional diameter increases by 0.033 mm.

3. The inhalation drug delivery device according to any one of claims 1 or 2, characterized in that, The drug particles delivered by the inhalation drug delivery device are inhaled powder aerosols.

4. A method for designing an inhalation drug delivery device, employing an inhalation drug delivery device as described in any one of claims 1 or 2, characterized in that, Includes the following steps: S1: Obtain the structural parameters of each part of the inhalation drug delivery model and establish the initial inhalation drug delivery model; S2: Determine the computational domain based on the initial inhalation drug delivery model; S3: Set the inhaled drug particle flow rate and the number of inhaled drug particles in the initial inhalation drug delivery model; S4: Based on the inhaled drug particle flow rate and the number of inhaled drug particles, the initial inhalation drug delivery model is simulated for inhalation drug delivery. The lattice Boltzmann method-immersion boundary method-large eddy simulation multi-physics coupling mechanism is used to simulate the airflow field and drug particle motion in the computational domain of the initial inhalation drug delivery model, so as to obtain the transient flow field data and drug particle motion data of the computational domain. S5: Establish a dynamic model of the drug particles and capsules in the computational domain, and obtain the resultant force on the drug particles in the computational domain based on the dynamic model of the drug particles and capsules. S6: Set at least one performance evaluation parameter, evaluate the transient flow field data, the drug particle motion data and the resultant force according to the performance evaluation parameter, and obtain the performance evaluation result; S7: Based on the performance evaluation results, adjust the structural parameters of the initial inhalation drug delivery model until the performance evaluation results meet the preset performance indicators; S8: Based on the structural parameters that meet the preset performance indicators, establish an optimized inhalation drug delivery model.

5. The design method of an inhalation drug delivery device according to claim 4, characterized in that, The computational domain is the square cavity at the nozzle of the initial inhalation drug delivery model and the internal region of the nozzle.

6. The design method of an inhalation drug delivery device according to claim 4, characterized in that, The aforementioned multiphysics coupling mechanism of the lattice Boltzmann method-immersion boundary method-large eddy simulation specifically includes: The airflow field in the computational domain of the initial inhalation drug delivery model was simulated using the lattice Boltzmann method and the large eddy simulation method to obtain transient flow field data; The expression for the transient flow field data is: ； In the formula, The location of the drug particles ,time Along the discrete velocity direction The distribution function, It's a relaxation time. It is the equilibrium distribution function. It is a volume force term. It is the rate of change over time; The motion of drug particles in the computational domain of the initial inhalation drug delivery model is simulated using the immersion boundary method to obtain the drug particle motion data; the expression for the immersion boundary method is: ； In the formula, This represents the Dirac function.

7. The design method of an inhalation drug delivery device according to claim 4, characterized in that, The kinetic model formula for the drug particles and capsules is as follows: ； ； In the formula, , , , These are the mass, moment of inertia, translational velocity, and angular velocity of the drug particle. It is the resultant force acting on the drug particles. It is the resultant torque.

8. The design method of an inhalation drug delivery device according to claim 4, characterized in that, The combined force acting on the drug particles Including: fluid-structure interaction force ,gravity Interparticle forces and electrostatic attraction and centrifugal force .

9. The design method of an inhalation drug delivery device according to claim 4, characterized in that, The performance evaluation parameters include: the instantaneous angular velocity and translational trajectory of the drug particles, the percentage of the mass of the drug particles in the outlet prescription cavity of the initial inhalation drug delivery model relative to the total mass of the emitted drug particles, the residence time distribution and spatial distribution of the drug particles in the prescription cavity, and the transient velocity distribution of the computational domain.

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