Drug deposition evaluation device and method based on nasal cavity standard structure model

Abstract

The invention discloses a medicine deposition evaluation device and method based on a nasal cavity standard structure model, and relates to the technical field of nasal preparation quality control, and the device comprises a nasal cavity structure module, a respiratory airflow control module, an image acquisition module and a data analysis module; wherein the nasal cavity structure module is used for calibrating a nasal cavity standard structure model, generating a plurality of nasal cavity structure blocks through 3D printing according to parameters of the nasal cavity standard structure model, and inputting a nasal preparation at the same time; the respiratory airflow control module is used for being connected with the nasal cavity structure module and controlling the respiratory flow of the nasal cavity structure module. According to the method, the texture mapping and the UV expansion technology are combined, accurate space positioning of the medicine deposition part on the surface of the nasal cavity structure module is achieved, the calculation accuracy of the deposition amount is remarkably improved through a partition quantitative analysis method, and reliable technical support is provided for nasal preparation medicine deposition evaluation.

Description

Technical Field

[0001] This invention relates to the field of nasal preparation quality control technology, and more specifically, to a drug deposition evaluation device and method based on a standard nasal cavity structural model. Background Technology

[0002] Nasal formulations are not only the preferred method of drug delivery for treating local inflammation, but also an important route for improving drug absorption and targeted brain delivery. However, the human nasal airway structure is complex, and different deposition sites have different absorption efficiencies. Drugs can only exert their full therapeutic effect when delivered to the target area in the nasal cavity; therefore, evaluating the characteristics of drug deposition in the nasal cavity is extremely important for nasal drug delivery. However, current quality evaluation standards for nasal formulations in various pharmacopoeias mainly focus on the formulation's own properties such as dose uniformity and microbial limits, without providing a clear evaluation method for the distribution of drug deposition in the nasal cavity.

[0003] A nasal cavity model, a model simulating the actual structure and shape of the human nasal cavity, has been widely used to study the in vitro deposition and distribution of nasal medications. Most previous studies utilized CT or MRI data from a single individual to 3D print transparent nasal cavity models. However, nasal cavity structure is influenced by factors such as age, sex, and ethnicity; therefore, current research focuses on expanding sample diversity to find a more representative standard structural model of the nasal cavity. Belgian researchers constructed a high-quality statistical shape model of the human nasal cavity based on CT data from 46 local subjects and analyzed the effects of age and sex on nasal cavity structural shape. A German study constructed a statistical shape model of a healthy nasal cavity using CT data from 25 healthy local subjects. Other studies have developed the Alberta ideal nasal cavity for evaluating local drug deposition within the nasal cavity; this model is an idealized geometric model of the nasal cavity constructed based on CT scans of ten adults' nasal cavities. However, the sample size of existing models is limited, and it has not been confirmed that the sample size is sufficient to construct a representative nasal cavity model, lacking statistical significance. Furthermore, there are few studies on the nasal cavity structure of Chinese people, lacking typical characteristics of the Chinese population. In addition, existing nasal cavity models are mostly disassembled by planar cutting, and many tortuous and narrow airway structures are hidden inside the model, making it difficult to see the inner surface of the nasal cavity.

[0004] In vitro imaging is currently considered an ideal method for evaluating the deposition and distribution of nasal formulations within the nasal cavity. Gamma scintillation imaging and SPECT / CT-based imaging methods can quantify radioactive tracers deposited in nasal cavity models. However, these methods require the use of radioactive elements, involve complex experimental procedures, and have high requirements for imaging equipment, leading to their gradual replacement by optical imaging combined with transparent nasal cavity models. One study utilized the property of a water-soluble ointment turning purple upon contact with water, uniformly applying the ointment to a transparent nasal cavity model, capturing the deposition pattern of the nasal spray with a digital camera, and using Photoshop to quantify the area of ​​the purple region in the image as a deposition evaluation index. However, current techniques can only capture the deposition distribution at a single cross-section of the nasal cavity. The inner surface of the nasal cavity is complex and tortuous; acquiring images from a single perspective inevitably results in overlapping and obstruction, making it impossible to clearly obtain the specific location of drug deposition on the inner surface. This lossily compresses the originally three-dimensional deposition information into two dimensions, thus affecting the accuracy of quantitative analysis results.

[0005] No effective solutions have yet been proposed to address the problems in the relevant technologies. Summary of the Invention

[0006] To address the problems in related technologies, this invention proposes a drug deposition evaluation device and method based on a standard nasal cavity structural model, in order to overcome the aforementioned technical problems existing in the prior art.

[0007] The technical solution of this invention is implemented as follows:

[0008] One aspect of the present invention:

[0009] A drug deposition evaluation device based on a standard nasal cavity structural model includes: a nasal cavity structure module, a respiratory airflow control module, an image acquisition module, and a data analysis module, wherein:

[0010] The nasal cavity structure module is used to calibrate the standard nasal cavity structure model and, based on the parameters of the standard nasal cavity structure model, to generate several nasal cavity structure blocks through 3D printing, while simultaneously inputting nasal preparations.

[0011] The breathing airflow control module is used to connect to the nasal cavity structure module and control the breathing flow of the nasal cavity structure module;

[0012] The image acquisition module is used to acquire images of several nasal cavity structure blocks of the nasal cavity structure module and transmit the images to the data analysis module;

[0013] The data analysis module is used to obtain and quantify the spatial deposition pattern of the drug based on the acquired images.

[0014] Furthermore, it also includes: a temperature and humidity control module, wherein:

[0015] The temperature and humidity control module is used to connect to the nasal cavity structure module and control the temperature and humidity environmental parameters of the nasal cavity structure module.

[0016] Furthermore, the standard nasal cavity structural model includes: a male standard nasal cavity structural model and a female standard nasal cavity structural model.

[0017] Furthermore, calibrating the standard nasal cavity structural model includes the following steps:

[0018] Acquire head and neck CT image data and establish a three-dimensional mesh model of the nasal airway using medical image segmentation technology;

[0019] The average structure model of the nasal cavity is constructed through vector averaging, and is represented as follows:

[0020]

[0021] Where x, y, z are the three-dimensional coordinates of the grid points;

[0022] The sample size is quantitatively evaluated by nasal cavity structural parameters and morphological similarity indicators, and the average nasal cavity structural model under this sample size is used as the standard nasal cavity structural model for males or females.

[0023] Furthermore, the plurality of nasal cavity structural blocks include at least: the left and right regions are divided into the uppermost block, the upper block, the middle block and the lower block along the point of greatest curvature of the superior, middle and inferior nasal meatuses; the middle region is divided into the nasal septum block and the nasopharyngeal block along the posterior nasal aperture.

[0024] Furthermore, the data analysis module acquires and quantifies the spatial deposition pattern of the drug, including the following steps:

[0025] Drug deposition information on the surface of nasal cavity structural blocks is pre-baked using Blender textures, and drug spatial deposition maps are obtained by UV unwrapping.

[0026] Use Photoshop to extract pixels that are similar in color to the drug and assign different grayscale values ​​based on how closely they resemble the drug's color.

[0027] The deposition score is defined as the proportion of the sum of gray values ​​of pixels in each partition to the total sum of gray values ​​of all regions in a single nasal cavity. It is expressed as:

[0028]

[0029] Among them, G p K represents the sum of gray values ​​of drug pixels deposited in a single nasal cavity partition p, and K represents the number of all partitions in a single nasal cavity.

[0030] Another aspect of the present invention:

[0031] A method for evaluating drug deposition based on a standard nasal cavity structural model includes the following steps:

[0032] A standard nasal cavity structure model is pre-calibrated, and based on the parameters of the standard nasal cavity structure model, a nasal cavity structure module is formed by 3D printing, which includes several nasal cavity structure blocks and a shell for fixing.

[0033] The respiratory flow rate of the nasal cavity structure module is controlled by the respiratory airflow control module;

[0034] Input nasal preparations into the nasal cavity structure module;

[0035] Images of multiple nasal cavity structural blocks of the nasal cavity structural module are acquired through the image acquisition module;

[0036] Based on the acquired images, the spatial deposition pattern of the drug is obtained and quantified.

[0037] The method of controlling the respiratory flow of the nasal cavity structure module through the respiratory airflow control module further includes:

[0038] The temperature and humidity environmental parameters of the nasal cavity structure module are controlled by the temperature and humidity control module.

[0039] The beneficial effects of this invention are:

[0040] This invention establishes a standard nasal cavity structural model based on statistical analysis of nasal CT data, improving upon the geometric deviations caused by insufficient sample representativeness in existing models. This provides a foundational model that conforms to the anatomical characteristics of specific populations for nasal cavity computational fluid dynamics research and drug deposition evaluation. Secondly, through a detachable modular nasal cavity structural module design, it overcomes the technical limitations of insufficient exposure of anatomical structures in traditional models, fully preserving the anatomical details of complex areas such as the nasal turbinates and olfactory region, and supporting multi-angle visualization of the nasal cavity's inner surface. Finally, by combining texture mapping and UV unwrapping techniques, precise spatial positioning of drug deposition sites on the surface of the nasal cavity structural module is achieved, and the accuracy of deposition calculation is significantly improved through a partitioned quantitative analysis method, providing reliable technical support for the evaluation of drug deposition in nasal formulations. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1This is a graph showing the changes in mucosal area, volume, root mean square error (RMSE), and Jaccard coefficient of the average nasal cavity structure models of male and female patients according to Embodiment 1 of the present invention. In the graph, A is the change in mucosal area with sample size; B is the change in volume with sample size; C is the change in RMSE with sample size; and D is the change in Jaccard coefficient with sample size.

[0043] Figure 2 This is a standard structural model of the male and female nasal cavities constructed according to Embodiment 1 of the present invention, and coronal cross-sectional views at different locations thereon;

[0044] Figure 3 This is a schematic diagram of the nasal cavity structure module of a drug deposition evaluation device based on a standard nasal cavity structure model according to Embodiment 1 of the present invention. In the figure, A is a schematic diagram of the breakdown of each nasal cavity structure block; B is a schematic diagram of the assembly; L represents the left nasal cavity module; R represents the right nasal cavity module; and M represents the nasal septum region module.

[0045] Figure 4 This is a schematic diagram of the deposition experiment of mometasone furoate nasal spray according to Embodiment 3 of the present invention;

[0046] Figure 5 This is a methodological verification diagram of mometasone furoate nasal spray according to Embodiment 3 of the present invention. In the diagram, A is a physical image of the deposition; B is the correlation between the deposition fractions in each region by the imaging method and the chemical method.

[0047] Figure 6 This is a blank right nasal cavity drug spatial deposition distribution map according to Embodiment 4 of the present invention (using a male drug spatial deposition distribution map as an example);

[0048] Figure 7 This is a drug spatial deposition map and deposition fraction of each region for mometasone furoate nasal spray according to Embodiment 4 of the present invention. In the figure, A is the drug spatial deposition map; B is the deposition fraction in the male nasal cavity deposition evaluation device; and C is the deposition fraction in the female nasal cavity deposition evaluation device.

[0049] Figure 8 This is a schematic diagram of the deposition experiment of hydroxypropyl methylcellulose (HPMC) nasal powder inhaler according to Example 5 of the present invention;

[0050] Figure 9 This is a methodological verification of the HPMC nasal powder spray according to Embodiment 5 of the present invention. In the figure, A is a picture of the actual deposition; B is the correlation between the deposition fraction of each region by the imaging method and the chemical method.

[0051] Figure 10This figure shows the drug spatial deposition map and deposition fraction of each region of the HPMC nasal powder spray according to Embodiment Six of the present invention. In the figure, A is the drug spatial deposition map; B is the deposition fraction in the male nasal cavity deposition evaluation device; and C is the deposition fraction in the female nasal cavity deposition evaluation device. Detailed Implementation

[0052] 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. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention are within the scope of protection of the present invention.

[0053] Example 1

[0054] According to an embodiment of the present invention, a drug deposition evaluation device based on a standard nasal cavity structural model is provided.

[0055] like Figures 1-3 As shown, the drug deposition evaluation device based on the standard nasal cavity structural model according to an embodiment of the present invention includes: a nasal cavity structure module, a respiratory airflow control module, an image acquisition module, and a data analysis module, wherein:

[0056] The nasal cavity structure module is used to calibrate the standard nasal cavity structure model and, based on the parameters of the standard nasal cavity structure model, to generate several nasal cavity structure blocks through 3D printing, while simultaneously inputting nasal preparations;

[0057] Specifically, this technical solution uses 3D printing to generate several nasal cavity structural blocks, which are then fixed in place by a shell.

[0058] The breathing airflow control module is used to connect to the nasal cavity structure module and control the breathing flow of the nasal cavity structure module; the controllable breathing flow range is 5-30L / min.

[0059] The image acquisition module is used to acquire images of several nasal cavity structural blocks from the nasal cavity structure module and transmit the images to the data analysis module.

[0060] In this technical solution, the image acquisition module can automatically rotate at a set angle to change the shooting angle; the object being photographed can rotate 360° at set intervals to capture images from two different angles in two dimensions.

[0061] Specifically, the image acquisition module's image acquisition method includes: taking 1-5 images from different angles around each nasal cavity structure block under uniform lighting and a solid color background using a camera; then using MeshLab to obtain the camera's spatial position and pose parameters for each image; and finally using Metashape to map the images onto the digital model of the nasal cavity structure module.

[0062] It also includes a temperature and humidity control module; wherein the temperature and humidity control module is used to connect to the nasal cavity structure module and control the temperature and humidity environmental parameters of the nasal cavity structure module.

[0063] Specifically, the temperature and humidity control module can achieve precise temperature control from 20-40℃ and humidity control from 10-100%.

[0064] In this technical solution, the specific steps for selecting a representative standard nasal cavity structure model of Han Chinese are as follows:

[0065] First, we analyzed head and neck computed tomography (CT) scans of 128 subjects (64 adult Chinese men and 64 adult Chinese women, aged 20 to 78 years) with no prior history of respiratory illness. Inclusion criteria: CT data did not show significant nasal septum deviation, mucosal edema, or turbinate hypertrophy. Exclusion criteria: Patients with allergic rhinitis, nasal tumors, severe nasal trauma, or postoperative nasal diseases. Using MimicsResearch software, we segmented binary images of the nasal airways from the head and neck CT scans of Han Chinese subjects and converted these images into triangular mesh models. Materialise3-Matic software was used to repair the surface of the nasal airway mesh models.

[0066] Next, a nasal airway structure mesh was randomly selected as a template. Using the best-fit alignment function, the nasal airway structures of 64 Chinese males and 64 Chinese females were aligned with the template mesh to the same coordinate system through translation and rotation. The Trim function in Materialise3-Matic software was used to trim away redundant laryngeal structures from all aligned Chinese nasal airways in one step, resulting in 128 Chinese nasal airway models containing identical and complete nasal structures. Furthermore, the AdaptiveRemesh function was used to unify the mesh shape of all models. The FixWizard function was then used for mesh repair. Nasal mucosal area and volume were selected as representative nasal structural parameters to examine the effects of age and sex.

[0067] Secondly, an average nasal cavity structure model was constructed using SlicerSALT software based on the statistical shape model principle. Using the Registration-based Correspondence function in SlicerSALT, a randomly selected nasal airway model was used as a template model. Non-rigid registration was performed on 128 nasal airway models from Han Chinese individuals using differential homeomorphism mapping, registering the template model to each target model to obtain models with one-to-one grid point correspondence. Then, the ProcrustesRegistration function in SlicerSALT was used to rigidly align all models. The average value of all model vectors was calculated to obtain the average nasal cavity structure model for Han Chinese individuals, represented as:

[0068]

[0069] Where x, y, and z are the three-dimensional coordinates of the grid points. A parametric three-dimensional data set is used to describe the nasal cavity morphology model. Furthermore, using the calculated average nasal cavity structure model of Han Chinese as a template, the non-rigid registration and rigid alignment steps are repeated. The models are then classified according to gender, and the average values ​​of the male and female model vectors are calculated separately to obtain the average nasal cavity structure models for males and females.

[0070] Finally, 2, 3, ..., m, ..., 63, 64 models were randomly selected from the 64 male nasal airway models, and denoted as S. m Using the method described above, the vector mean of m grid models is calculated to obtain the average nasal cavity structure models for males with sample sizes of 2, 3, ..., 64. The above steps are repeated three times with random sampling. The same operation is performed on 64 female nasal airway models to obtain three sets of average nasal cavity structure models for females with sample sizes of 2, 3, ..., 64. Nasal mucosal area, volume, root mean square error, and Jaccard coefficient are used as parameters to evaluate the average nasal cavity structure models for males and females calculated with different sample sizes. This study investigates the impact of different sample sizes on the average nasal cavity structure of males and females to avoid morphological bias caused by insufficient sample size.

[0071] The root mean square error (RMSE) is expressed as:

[0072]

[0073] The Jaccard coefficient is expressed as:

[0074]

[0075] In the above formula, n is the total number of grid points in each model, and m is the number of samples used in the calculation. mThis represents the average nasal cavity structure model calculated from m samples.

[0076] Table 1 shows the comparison of nasal cavity structural parameters between men and women. The nasal mucosal area and volume are generally larger in men than in women. The average nasal mucosal area in men is 18978±209 mm². 2 The average nasal mucosal area for women is 17604±162 mm. 2 The average nasal cavity volume for men is 30413±614 mm. 3 The average nasal cavity volume for women is 27285±543 mm. 3 Significant differences were found in both the nasal mucosal area and volume between men and women (p<0.05). Furthermore, nasal samples were divided into six age groups, and one-way ANOVA was performed on the nasal mucosal area and volume in both men and women in relation to age. The results showed no significant age-related correlation between changes in nasal mucosal area and volume in either gender, indicating that the nasal cavity structure tends to stabilize after adulthood, without a significant trend of expansion or contraction. Therefore, it is necessary to construct standard nasal cavity structural models for men and women separately, considering gender factors.

[0077] Table 1. Comparison of average nasal mucosal area and average nasal cavity volume between men and women (mean ± standard error)

[0078]

[0079] The results of the changes in the average nasal cavity structure of men and women with sample size are as follows: Figure 1 As shown, with the increase of sample size, the mucosal area and volume of the average nasal cavity structure models for both men and women gradually stabilized after initial fluctuations. When the sample size reached approximately 50, the mucosal area of ​​the average male nasal cavity structure model stabilized at 18311 mm². 2 Around 17007mm for women 2 about( Figure 1 A) When the sample size reaches approximately 55, the average volume of the male nasal cavity structural model stabilizes at 30208 mm. 3 Around 26960mm for women 3 about( Figure 1 B). Furthermore, as the sample size increases, the root mean square error between the average nasal cavity structure models for both men and women calculated from adjacent sample sizes decreases and approaches 0 mm. When the sample size increases from 1 to 20, the distance error decreases significantly, and then the error change gradually flattens and tends to stabilize. Figure 1C), when the sample size reached 61, the RMSE was less than 0.05 mm. Meanwhile, the similarity between the average nasal cavity structure models of males and females calculated from adjacent sample sizes increased and approached 1. When the sample size increased from 1 to 15, the similarity increased significantly, then the change in similarity gradually leveled off and tended to stabilize, and when the sample size reached 64, the similarity was greater than 0.99. Figure 1 D). In summary, the number of 64 CT samples is sufficient to ensure that the four evaluation parameters—nasal mucosal area, volume, root mean square error between the average nasal cavity structural models of adjacent sample sizes, and Jaccard coefficient—converge to acceptable levels. Therefore, the average nasal cavity structural models for men and women calculated from the 64 nasal cavity CT reconstruction data can be confirmed as the standard nasal cavity structural models for Han Chinese (structural parameters are shown in Table 2). The coronal section images and areas of the standard nasal cavity structural model for Han Chinese are shown in Table 2. Figure 2 Table 3.

[0080] Table 2 Structural parameters of standard male and female nasal cavity models

[0081]

[0082] Table 3. Coronal section locations and regions of standard nasal cavity structural models for males and females.

[0083]

[0084]

[0085] In addition, such as Figure 3 As shown, for the aforementioned nasal cavity structural blocks, the human nasal cavity structure is complex and tortuous, making it difficult to directly observe drug deposition on its inner surface. By disassembling the nasal cavity structure along the points of greatest curvature in the superior, middle, and inferior nasal passages, the inner surface of the nasal cavity can be fully exposed. Based on this, the standard male and female nasal cavity structural models are disassembled in the same way. Each nasal cavity is divided into an uppermost block (R / L1), an upper block (R / L2), a middle block (R / L3), and a lower block (R / L4). The middle region is further divided along the posterior nasal aperture into a nasal septum block (M1) and a nasopharyngeal block (M2). The disassembly lines are marked on the standard male nasal cavity structural model, and then the model is disassembled along these lines. Furthermore, in Blender software, the divided regions are created into a model that can be easily assembled into a complete block, resulting in the male nasal cavity structural module. The female nasal cavity structural module is created using the same method. In addition, a shell for fixing the nasal cavity structural module is designed. Using Future8000 black resin as the material, male and female nasal cavity structure modules were 3D printed using photopolymerization stereolithography technology.

[0086] In addition, the data analysis module is used to obtain and quantify the spatial deposition pattern of the drug based on the acquired images.

[0087] Among them, the drug spatial deposition map is a two-dimensional unfolding of the three-dimensional standard nasal cavity structural model. The left and right nasal cavities are divided into seven regions, namely the nasal vestibule, olfactory region, superior turbinate, middle turbinate, inferior turbinate, nasal septum and nasopharynx, according to the physiological structural characteristics of the nasal cavity and the drug permeability.

[0088] In practical applications, the drug spatial deposition map partitioning can be adjusted according to actual needs.

[0089] The data analysis module acquires and quantifies drug spatial deposition patterns, including the following steps:

[0090] Drug deposition information on the surface of nasal cavity structural blocks is pre-baked using Blender textures, and drug spatial deposition maps are obtained by UV unwrapping.

[0091] Use Photoshop to extract pixels that are similar in color to the drug and assign different grayscale values ​​based on how closely they resemble the drug's color.

[0092] The deposition score is defined as the proportion of the sum of gray values ​​of pixels in each partition to the total sum of gray values ​​of all regions in a single nasal cavity. It is expressed as:

[0093]

[0094] Where represents the sum of gray values ​​of drug pixels deposited in a single nasal cavity partition p, and K represents the number of all partitions in a single nasal cavity.

[0095] Using the above-mentioned scheme, the deposition fraction index can be used to precisely quantify the deposition of nasal formulations in different nasal cavity structural blocks, comprehensively reflecting the distribution characteristics of the drug in key absorption areas and non-target areas. This index not only has good repeatability and discrimination, which can be used to guide the optimization design of formulations and devices, but also serves as a key standard for measuring the quality of nasal formulations, applicable to multiple stages such as product development, consistency evaluation, and quality control.

[0096] Example 2

[0097] According to an embodiment of the present invention, a method for evaluating drug deposition based on a standard nasal cavity structural model is provided, comprising the following steps:

[0098] A standard nasal cavity structure model is pre-calibrated, and based on the parameters of the standard nasal cavity structure model, a nasal cavity structure module is formed by 3D printing, which includes several nasal cavity structure blocks and a shell for fixing.

[0099] The respiratory flow rate of the nasal cavity structure module is controlled by the respiratory airflow control module;

[0100] Input nasal spray formulation into the nasal cavity structure module;

[0101] Images of multiple nasal cavity structural blocks of the nasal cavity structural module are acquired through the image acquisition module;

[0102] Based on the acquired images, the spatial deposition pattern of the drug is obtained and quantified.

[0103] The method of controlling the respiratory flow of the nasal cavity structure module through the respiratory airflow control module further includes controlling the temperature and humidity environmental parameters of the nasal cavity structure module through the temperature and humidity control module.

[0104] Specifically, the above-mentioned drug deposition evaluation method is applicable to all types of nasal preparations, including: liquids, solids (such as powders, lyophilized forms), semi-solids (such as gels, creams), aerosols and their combinations, covering administration by spraying, dripping, inhalation or application.

[0105] Example 3

[0106] like Figures 4-5 As shown in the embodiments of the present invention, a commercially available formulation of mometasone furoate nasal spray is provided as a nasal spray formulation and a male nasal cavity structure module to verify the correlation between the deposition quantification method based on water-based colorimetric imaging and the chemical quantification method. Specifically, as follows:

[0107] Apply KolorKut nasal spray evenly to the inner surface of each nasal cavity structural section of the male nasal cavity structural module using a brush. After assembling the model, seal it with wax, put on the outer shell, and secure it with rubber bands. Fix the model on the iron stand. According to the drug instructions, rotate the model and tilt it 10° relative to the horizontal plane. Connect the air pump and adjust the flow rate to 20L / min. Seal the left nostril with transparent tape. Keep the mometasone furoate nasal spray vertical and spray one puff into the right nostril. Figure 4The same procedure was repeated, spraying one puff into the left nostril. This process was repeated three times in parallel. The model was then disassembled. Under uniform lighting and a solid-color background, 1-5 images (image size: 3024x4032) were taken from different angles around each nasal cavity model using a camera. These images were sufficient to cover complete surface deposition information. The RasterAlignment function in MeshLab software was used to automatically align the acquired images with the 3D digital model of each corresponding nasal cavity structure module, obtaining the camera pose for each image. Next, using texture mapping, the images containing deposition information were mapped onto the corresponding 3D digital model of each male nasal cavity structure module. The UVunwrap function in Blender software was then used to flatten the model into a two-dimensional drug deposition map according to the actual partitions. Finally, pixels with colors similar to the drug were extracted and assigned different grayscale values ​​based on their similarity to the drug color. The proportion of the sum of the grayscale values ​​of pixels in each partition to the total grayscale values ​​of all areas in one nasal cavity was calculated; this was the deposition score.

[0108] After collecting surface texture data containing drug deposition distribution information, the inner surfaces of each block of the nasal cavity structural module were repeatedly rinsed with an appropriate volume of methanol until the inner surfaces were completely clean. Mometasone furoate from the inner surfaces of each block was recovered as completely as possible and transferred to a volumetric flask, then diluted to the mark. After vortexing to ensure thorough mixing, 1 mL of the eluent was transferred to an EP tube and centrifuged at 12000 rpm for 5 min. The supernatant was then used for high-performance liquid chromatography (HPLC) to determine the mometasone furoate content. The drug content deposited on each block was calculated. The chemical deposition fraction was defined as the proportion of the drug content in each zone to the total drug content in all regions of the unilateral nasal cavity, expressed as:

[0109]

[0110] Among them, C p This indicates the amount of drug deposited in unilateral nasal cavity partition p, and K represents the number of all partitions in unilateral nasal cavity.

[0111] The test paste is a yellow paste that turns purplish-red upon contact with water. Based on this color-changing principle, when mometasone furoate nasal spray is sprayed into a male nasal cavity structure module coated with the test paste, the paste at the deposition site turns purplish-red, while areas not deposited remain yellow. Figure 5A) This color change is sensitive and clearly visible, making it possible to acquire deposition images of nasal liquid formulations using imaging methods, and further obtain and quantify the spatial deposition map of the drug. The results of the imaging method for intranasal deposition distribution of mometasone furoate nasal spray were compared with the results of the chemical quantitative method, and a quantitative correlation was established using linear regression. The results show that the deposition fractions of each region obtained by the imaging deposition quantification method based on the color change of the test paste and the chemical quantitative method have a certain correlation, R... 2 It is 0.9316 ( Figure 5 B).

[0112] Example 4

[0113] like Figures 6-7 As shown in the embodiments of the present invention, a commercially available formulation of mometasone furoate nasal spray is provided as a nasal spray formulation and a male nasal cavity structure module for characterizing the spatial deposition pattern of the nasal liquid formulation. Specifically, as follows:

[0114] KolorKut nasal spray was evenly applied to the inner surface of each section of the male nasal cavity structure module using a brush. After assembling the model, it was wax-sealed, fitted with an outer shell, and secured with rubber bands. The model was fixed on an iron stand. Following the drug instructions, the model was rotated and tilted 10° relative to the horizontal plane. An air pump was connected, and the flow rate was adjusted to 20 L / min. The left nostril was sealed with transparent tape. The mometasone furoate nasal spray was kept vertical, and one puff was sprayed into the right nostril. The same operation was repeated, spraying one puff into the left nostril. The above operation was repeated, with three parallel experiments. The model was disassembled. Under uniform lighting and a solid-color background, 1-5 images (image size: 3024x4032) were taken from different angles around each nasal cavity model using a camera. These images were sufficient to cover complete surface deposition information. The RasterAlignment function in MeshLab software was used to automatically align the acquired images with the 3D digital model of each corresponding male nasal cavity structure module to obtain the camera pose of each image. Next, using texture mapping, the image containing deposition information was mapped onto the corresponding 3D digital model of each male nasal cavity structural module. Furthermore, the UVunwrap function in Blender software was used to divide the model into seven regions (the left and right nasal cavities are each divided into seven regions based on the physiological structural characteristics and drug permeability of the nasal cavity: nasal vestibule, olfactory region, superior turbinate, middle turbinate, inferior turbinate, nasal septum, and nasopharynx) according to the defined partitions. Figure 6 The image was flattened into a two-dimensional spatial deposition map of the drug. Finally, pixels with colors similar to the drug were extracted and assigned different grayscale values ​​based on their similarity to the drug color. The deposition score was calculated, similar to Example 1. The deposition distribution of mometasone furoate nasal spray in the female nasal cavity structural module (n=3) was investigated using the same method.

[0115] Based on the color-changing principle of the test paste, the spatial deposition pattern of mometasone furoate nasal spray was acquired and quantified using imaging methods. The results are as follows: Figure 7 As shown, significant drug deposition was observed in the nasal vestibule, middle turbinate, inferior turbinate, and nasal septum. Over 50% of the total drug deposition was found in the nasal vestibule and nasal septum, while no deposition was observed in the olfactory region, superior turbinate, or nasopharynx. Comparison of mometasone furoate deposition distribution in male and female nasal cavity structural modules revealed that although drug deposition was higher in the male nasal vestibule than in females, statistical results showed no significant difference in deposition fraction across any region of the male and female nasal cavity structural modules (Table 4). This indicates that the differences in male and female nasal cavity structures did not significantly affect the drug deposition distribution. Furthermore, the deposition distribution of mometasone furoate in the left and right nasal cavities was relatively consistent across both male and female nasal cavity structural modules, with no statistically significant difference (p > 0.05).

[0116] Table 4. Deposition fractions of mometasone furoate nasal spray in different regions of the spatial deposition map (imaging method) (n=3)

[0117]

[0118] In the table, p1: p-value of the difference in deposition fraction between male and female nasal cavities; p2: p-value of the difference in deposition fraction between male left nasal cavity and male right nasal cavity; p3: p-value of the difference in deposition fraction between female left nasal cavity and female right nasal cavity.

[0119] Example 5

[0120] like Figures 8-9 As shown, according to embodiments of the present invention, HPMC nasal powder spray is provided as a nasal spray formulation and a male nasal cavity structure module, and the correlation between the imaging-based quantitative method for nasal powder spray deposition and the chemical quantitative results is verified. Specifically, as follows:

[0121] After uniformly coating the inner surfaces of each section of the male nasal cavity structure module with 1% silicone oil and hexane and allowing it to dry, the model was assembled, wax-sealed, and then fitted with an outer shell and secured with rubber bands. The model was fixed to an iron stand. Following the drug instructions, the model was rotated and tilted 10° relative to the horizontal plane. An air pump was connected, and the flow rate was adjusted to 15 L / min. Inhalation was performed through both nostrils. The HPMC nasal powder was kept vertical, and three sprays were injected into the right nostril. The same procedure was repeated, injecting three sprays into the left nostril. The above procedure was repeated three times in parallel. Figure 8The model was disassembled, and under uniform lighting and a solid-color background, 1-5 images (image size: 3024×4032) were taken from different angles around each nasal cavity model using a camera. These images were sufficient to cover complete surface deposition information. The RasterAlignment function in MeshLab software was used to automatically align the acquired images with the 3D digital model of each corresponding nasal cavity structure module to obtain the camera spatial position and orientation of each image. Next, using texture mapping, the images containing deposition information were mapped onto the corresponding 3D digital model of each nasal cavity structure module. Furthermore, the UVunwrap function in Blender software was used to flatten the model into a two-dimensional drug deposition map according to the actual partitions of the device. Finally, pixels with colors similar to the drug were extracted, and different grayscale values ​​were assigned based on their similarity to the drug color. Similar to Example 1, the proportion of the sum of the grayscale values ​​of pixels in each partition to the total grayscale values ​​of all areas of one nasal cavity was calculated using the formula; this proportion is the deposition score.

[0122] After collecting surface texture data containing drug deposition distribution information, appropriate volumes of 50 mmol·L⁻¹ were used. -1 Rinse the inner surfaces of each section of the nasal cavity structural module with sodium chloride solution until the inner surfaces are completely clean, recovering as much HPMC as possible from the inner surfaces of each section into a volumetric flask and making up to the mark. Invert and shake to mix the liquid in the flask thoroughly, place it in an 80°C water bath to dissolve, cool, and transfer 1 mL to an EP tube. Centrifuge at 12000 rpm for 5 min, and use high-performance liquid chromatography (HPLC) to determine the HPMC content. Calculate the drug content and chemical deposition fraction deposited on each section.

[0123] The commercially available HPMC nasal powder spray used is a white powder. After being sprayed into the nasal cavity structure module, it forms a sharp contrast with the black background of the device, and the deposited area will have a clearly visible white color. Figure 9 A). Therefore, the three-dimensional deposition distribution information of the drug can be directly collected by acquiring deposition images of the inner surface of the acquisition device, obtaining a spatial deposition map of the drug and performing quantification. The results of the imaging-based quantification method and the chemical quantification method for intranasal deposition distribution of HPMC nasal powder were used to establish a quantitative correlation using linear regression. The results show that the imaging-based deposition quantification method is reliable. In the deposition experiment of HPMC nasal powder, the imaging deposition fraction and the chemical deposition fraction in each region showed a good correlation, R... 2 It is 0.9642 ( Figure 9 B).

[0124] Example 6

[0125] like Figure 10As shown, according to an embodiment of the present invention, HPMC nasal powder inhaler is provided as a nasal spray formulation and a male nasal cavity structural module, and the spatial deposition pattern of the drug inhaler is characterized. Specifically, as follows:

[0126] After uniformly coating the inner surface of each section of the male nasal cavity structure module with 1% silicone oil and hexane and allowing it to dry, the model was assembled, wax-sealed, and then fitted with an outer shell and secured with rubber bands. The model was fixed to an iron stand, and according to the drug instructions, it was rotated and tilted 10° relative to the horizontal plane. An air pump was connected, and the flow rate was adjusted to 15 L / min. Inhalation was performed through both nostrils, and the HPMC nasal powder was kept vertical, spraying 3 sprays into the right nostril. The same procedure was repeated, spraying 3 sprays into the left nostril. The above operation was repeated three times in parallel. The model was then disassembled, and under uniform lighting and a solid-color background, 1-5 images (image size: 3024x4032) were taken from different angles around each nasal cavity model using a camera. These images were sufficient to cover complete surface deposition information. The RasterAlignment function in MeshLab software was used to automatically align the acquired images with the 3D digital model of each corresponding nasal cavity structure module to obtain the camera pose for each image. Next, using texture mapping, the image containing deposition information is mapped onto the corresponding 3D digital model of each nasal cavity structural module. Furthermore, the UVunwrap function in Blender software is used to divide the model into seven regions (the left and right nasal cavities are each divided into seven regions based on the physiological structure and drug permeability of the nasal cavity: nasal vestibule, olfactory region, superior turbinate, middle turbinate, inferior turbinate, nasal septum, and nasopharynx) according to the defined partitions. Figure 6 The image was flattened into a two-dimensional spatial deposition map of the drug. Finally, pixels with colors similar to the drug were extracted and assigned different grayscale values ​​based on their similarity to the drug color, and the deposition score was calculated. The same method was used to examine the deposition distribution of HPMC nasal powder in the female nasal cavity structural module (n=3).

[0127] The spatial deposition map of the drug inhaler for HPMC nasal powder was acquired and constructed using imaging methods, and the results are as follows: Figure 10As shown, the drug distribution is clearly visible. Unlike mometasone furoate nasal spray, this nasal powder spray deposits in all seven regions of the left and right nasal cavities. Notably, the drug can be delivered to the olfactory region. Specifically, the drug deposition fraction is high in the middle turbinate, inferior turbinate, and nasal septum, accounting for over 70% in total. Next, about 10% of the drug is deposited in the nasopharynx, while the least amount is deposited in the nasal vestibule. Comparing the deposition distribution of HPMC nasal powder spray in male and female nasal cavity structural modules reveals statistically significant differences in the drug deposition fraction in the left inferior turbinate region and the right nasal septum region of the male nasal cavity structural module (Table 5), both significantly higher than in women. It is speculated that this may be due to the differences in nasal cavity structure between men and women. Because the volume and surface area of ​​the male nasal cavity are larger than those of women, and the gap between the anterior end of the inferior nasal meatus and the nasal septum is also slightly larger, the powder is more easily dispersed in the inferior turbinate and nasal septum regions of the male nasal cavity structural module. Furthermore, regardless of whether it was a male or female nasal cavity structure module, the deposition distribution of HPMC nasal powder in the left and right nasal cavities was relatively consistent, with no statistically significant difference (p>0.05).

[0128] Table 5. Deposition fractions of HPMC nasal powder inhaler in different regions of the spatial deposition map (imaging method) (n=3)

[0129]

[0130]

[0131] In the table above, p1 represents the p-value of the difference in deposition fraction between males and females in each region; p2 represents the p-value of the difference in deposition fraction between males in the left nasal cavity and males in the right nasal cavity; and p3 represents the difference in deposition fraction between females in the left nasal cavity and females in the right nasal cavity.

[0132] In summary, by employing the above-described technical solution of the present invention, the following effects can be achieved:

[0133] This invention establishes a standard nasal cavity structural model based on statistical analysis of nasal CT data, improving upon the geometric deviations caused by insufficient sample representativeness in existing models. This provides a foundational model that conforms to the anatomical characteristics of specific populations for nasal cavity computational fluid dynamics research and drug deposition evaluation. Secondly, through a detachable modular nasal cavity structural module design, it overcomes the technical limitations of insufficient exposure of anatomical structures in traditional models, fully preserving the anatomical details of complex areas such as the nasal turbinates and olfactory region, and supporting multi-angle visualization of the nasal cavity's inner surface. Finally, by combining texture mapping and UV unwrapping techniques, precise spatial positioning of drug deposition sites on the surface of the nasal cavity structural module is achieved, and the accuracy of deposition calculation is significantly improved through a partitioned quantitative analysis method, providing reliable technical support for the evaluation of drug deposition in nasal formulations.

[0134] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Those skilled in the art, upon considering the disclosure in the specification and embodiments, will readily conceive of other embodiments of this disclosure. This application is intended to cover any variations, uses, or adaptations of this disclosure that follow the general principles of this disclosure and include common knowledge or customary techniques in the art not disclosed herein. The specification and embodiments are to be considered exemplary only, and the true scope and spirit of this disclosure are indicated by the claims.

[0135] It should be understood that this disclosure is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of this disclosure is limited only by the appended claims.

Claims

1. A drug deposition evaluation device based on a standard nasal cavity structural model, characterized in that, include: The module includes a nasal cavity structure module, a respiratory airflow control module, an image acquisition module, and a data analysis module, among which: The nasal cavity structure module is used to calibrate the standard nasal cavity structure model and generate several nasal cavity structure blocks by 3D printing based on the parameters of the standard nasal cavity structure model, while simultaneously inputting nasal preparations. The breathing airflow control module is used to connect to the nasal cavity structure module and control the breathing flow of the nasal cavity structure module; The image acquisition module is used to acquire images of several nasal cavity structure blocks of the nasal cavity structure module and transmit the images to the data analysis module; The data analysis module is used to obtain and quantify the spatial deposition pattern of the drug based on the acquired images.

2. The drug deposition evaluation device based on the standard nasal cavity structural model according to claim 1, characterized in that, Also includes: Temperature and humidity control module, including: The temperature and humidity control module is used to connect to the nasal cavity structure module and control the temperature and humidity environmental parameters of the nasal cavity structure module.

3. The drug deposition evaluation device and method based on the standard nasal cavity structural model according to claim 1, characterized in that, The standard nasal cavity structure model includes: a standard male nasal cavity structure model and a standard female nasal cavity structure model.

4. The drug deposition evaluation device based on the standard nasal cavity structural model according to claim 3, characterized in that, The calibration of the standard nasal cavity structural model includes the following steps: Acquire head and neck CT image data and establish a three-dimensional mesh model of the nasal airway using medical image segmentation technology; The average structure model of the nasal cavity is constructed through vector averaging, and is represented as follows: Where x, y, z are the three-dimensional coordinates of the grid points; The sample size is quantitatively evaluated by nasal cavity structural parameters and morphological similarity indicators, and the average nasal cavity structural model under this sample size is used as the standard nasal cavity structural model for males or females.

5. The drug deposition evaluation device based on the standard nasal cavity structural model according to claim 1, characterized in that, The aforementioned nasal cavity structural blocks include at least the following: the left and right regions are divided into the uppermost block, the upper block, the middle block, and the lower block along the point of greatest curvature of the superior, middle, and inferior nasal meatuses; the middle region is divided into the nasal septum block and the nasopharyngeal block along the posterior nasal aperture.

6. The drug deposition evaluation device based on the standard nasal cavity structural model according to claim 1, characterized in that, The data analysis module acquires and quantifies the spatial deposition pattern of the drug, including the following steps: Drug deposition information on the surface of nasal cavity structural blocks is pre-baked using Blender textures, and drug spatial deposition maps are obtained by UV unwrapping. Use Photoshop to extract pixels that are similar in color to the drug and assign different grayscale values ​​based on how closely they resemble the drug's color. The deposition score is defined as the proportion of the sum of gray values ​​of pixels in each partition to the total sum of gray values ​​of all regions in a single nasal cavity. It is expressed as: Among them, G p K represents the sum of gray values ​​of drug pixels deposited in a single nasal cavity partition p, and K represents the number of all partitions in a single nasal cavity.

7. A method for evaluating drug deposition based on a standard nasal cavity structural model, used in the evaluation method of the drug deposition evaluation device based on a standard nasal cavity structural model as described in any one of claims 1-6, characterized in that, Includes the following steps: A standard nasal cavity structure model is pre-calibrated, and based on the parameters of the standard nasal cavity structure model, a nasal cavity structure module is formed by 3D printing, silicone mold pouring, vacuum casting or injection molding, which includes several nasal cavity structure blocks and a shell for fixing. The respiratory flow rate of the nasal cavity structure module is controlled by the respiratory airflow control module; Input nasal spray formulation into the nasal cavity structure module; Images of multiple nasal cavity structural blocks of the nasal cavity structural module are acquired through the image acquisition module; Based on the acquired images, the spatial deposition pattern of the drug is obtained and quantified.

8. The drug deposition evaluation method based on the standard nasal cavity structural model according to claim 7, wherein controlling the respiratory flow rate of the nasal cavity structural module through the respiratory airflow control module further includes: The temperature and humidity environmental parameters of the nasal cavity structure module are controlled by the temperature and humidity control module.

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