Noninvasive drug transdermal transport device and method based on photoacoustic effect

Abstract

The invention discloses a noninvasive drug transdermal transport device and method based on a photoacoustic effect, and belongs to the field of drug delivery, and the noninvasive drug transdermal transport device comprises a substrate, and the substrate is plated with a film layer; the packaging substrate layer is divided into an upper layer and a lower layer; both the upper layer and the lower layer are designed to be ring-shaped, and a cavitation cavity is formed in the middle of the lower layer and used for storing medicine; the upper layer is used for embedding a substrate; the upper layer and the lower layer are combined together, and the surface, coated with the film, of the substrate faces the cavitation cavity; and the excitation light source system is used for focusing the light beam, so that the incidence point of the laser is subjected to three-dimensional adjustment, and the optimal device efficiency is achieved. The mask does not cause secondary damage to the skin, and has the advantages of high efficiency, low preparation cost, fast preparation process and wide selection of preparation materials.

Description

Technical Field

[0001] The present invention relates to the technical field of drug delivery, and more specifically, to a non-invasive drug transdermal transport device and method based on photoacoustic effect. Background Art

[0002] Currently, transdermal drug delivery primarily involves two methods: injection and oral administration. Numerous methods have been developed for injection, the most advanced of which is microneedling, which creates tiny skin openings to facilitate drug entry. Oral administration, on the other hand, is a slower method, lacking immediate effectiveness.

[0003] Ultrasound-enhanced permeation is a recently emerging area of research. The generation of ultrasound waves primarily relies on the piezoelectric and inverse piezoelectric effects, requiring the identification of suitable piezoelectric materials and the pre-configured circuitry within the designed device, which in turn requires an external power supply. These conventional design approaches significantly limit device size and pose risks of electrical leakage and burns during use. Summary of the Invention

[0004] The purpose of the present invention is to overcome the shortcomings of the existing technology and provide a non-invasive drug transdermal transport device and method based on the photoacoustic effect. The injection method is friendly and will not cause secondary damage to the skin. It also has the advantages of high efficiency, low preparation cost, fast production process, and a wide range of production materials.

[0005] The object of the present invention is achieved through the following solutions:

[0006] A non-invasive drug transdermal transport device based on photoacoustic effect, comprising:

[0007] a substrate, on which a film layer is plated;

[0008] The encapsulation substrate layer is divided into two layers, the upper and lower layers; both the upper and lower layers are designed in a ring shape, and the middle part of the lower layer is provided with a cavitation cavity for storing drugs; the upper layer is used to embed the substrate; the upper and lower layers are combined together, with the substrate coating side facing the cavitation cavity;

[0009] The excitation light source system is used to focus the light beam and adjust the incident point of the laser in three dimensions to achieve optimal device efficiency.

[0010] Furthermore, the excitation light source system specifically includes: a light source, three total reflection mirrors and a convex lens; the light emitted by the light source is incident on a convex lens through the three total reflection mirrors to focus the light beam; adjusting the angle of a single reflection mirror can make the pulsed laser move on a one-dimensional line, and adjusting the angles of two of the reflection mirrors can make the laser move in a two-dimensional plane. If the height of the convex lens is further adjusted to adjust the focal point, the end of the light beam can move in three-dimensional space.

[0011] Furthermore, it also includes a motor system. The excitation light source system is placed in a black box and the motor system is used to fine-tune the position of the total reflection mirror.

[0012] Furthermore, the substrate comprises quartz glass.

[0013] Furthermore, the film layer includes a gold film.

[0014] Furthermore, the packaging base layer includes a PDMS material packaging base layer; the shape of the PDMS material packaging base layer can be changed according to the patient's skin structure.

[0015] A non-invasive drug transdermal delivery method based on photoacoustic effect comprises the following steps:

[0016] S1, using the photo-induced ultrasonic effect and ultrasonic cavitation effect, uses materials with plasmon effect as the substrate for photoacoustic energy conversion, and selects laser energy and wavelength to generate ultrasonic waves of a certain frequency;

[0017] S2, when the ultrasound reaches a certain threshold, cavitation bubbles are generated in the liquid environment. The bursting of the bubbles releases energy, which promotes the transdermal transport of drugs.

[0018] Furthermore, in step S1, the ultrasonic wave of a certain frequency is specifically made to have an ultrasonic wave frequency of 80 kHz or higher.

[0019] Furthermore, the non-invasive drug transdermal transport device based on the photoacoustic effect as described in any of the above items is utilized, and the operating power of the laser of the excitation light source system is between 250mW and 300mW.

[0020] Furthermore, the laser includes a 532nm pulse laser.

[0021] The beneficial effects of the present invention include:

[0022] The present invention has both the effect of ultrasonic permeation and optical controllability, and can bring more precise control effects than other devices.

[0023] The device of the present invention can significantly promote the transdermal transport of small molecule drugs. Laboratory tests have shown that, under the same timeframe, the drug injection depth is 2-3 times greater than that achieved by free diffusion, and the injection volume is 8-10 times greater. Furthermore, the drug injection solution provided by the present invention can be used for a variety of small molecule drugs, including but not limited to vitamins and traditional Chinese medicine extracts, significantly improving the efficiency of cosmetic or subcutaneous medications.

[0024] The present invention is based on the principles of photo-induced ultrasound and ultrasonic cavitation. Materials with plasmon effects can serve as a substrate for photoacoustic energy conversion. By selecting appropriate laser energy and wavelength, ultrasound waves of a certain frequency can be generated. When the ultrasound waves reach a certain threshold, cavitation bubbles are generated in a liquid environment. The rupture of the bubbles releases a large amount of energy, promoting transdermal drug transport. Furthermore, the present invention combines photo-induced ultrasound and cavitation technologies, and their application in the medical industry is very broad, including in fields such as bioimaging. Furthermore, the device has low production costs, a fast production process, and a wide range of materials, resulting in high efficiency.

[0025] The technical solution of this invention is applicable to the beauty and medical industries for drug injection. Its efficiency is approximately 10 times that of free diffusion of drug gel into the skin, which can improve drug utilization per unit volume. Furthermore, it is more friendly to sensitive or injured skin, and the drug injection process does not cause secondary damage to the skin. By controlling the laser power, the action time can be effectively controlled, improving efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0027] Figure 1 Schematic diagram of the structure of the device according to the embodiment of the present invention;

[0028] Figure 2 This is a schematic diagram of the light source system structure of the device according to an embodiment of the present invention;

[0029] Figure 3 Schematic diagram of a non-contact ultrasonic wave generating method of a device according to an embodiment of the present invention;

[0030] Figure 4 Flowchart of the steps of the method according to an embodiment of the present invention. DETAILED DESCRIPTION

[0031] All features disclosed in all embodiments in this specification, or steps in all methods or processes implicitly disclosed, except for mutually exclusive features and / or steps, can be combined and / or expanded or replaced in any manner.

[0032] In order to solve the problems in the background, the inventors of this application conducted further research and found that:

[0033] The photoultrasound effect is a non-contact method for generating ultrasound waves. It uses light energy to stimulate thermal effects within a medium, thereby generating ultrasound waves. This application utilizes the principle of the photoultrasound effect to propose a new technical solution aimed at addressing the technical problem of damage to the skin barrier caused by microneedles and injections in existing drug delivery devices. The concept is to accelerate drug delivery through ultrasound without damaging the skin barrier. The specific implementation is as follows:

[0034] In the conception of the technical solution of this application, it is first necessary to design a base that is close to the skin, a suitable cavitation cavity size, consider the miniaturization of the device, and use vacuum evaporation technology for coating and packaging. It is also necessary to consider the excitation light source, such as using a 532nm pulsed laser for external excitation, and it is necessary to select a suitable coating material (such as gold) to absorb most of the laser energy and avoid damaging the skin due to excessive laser power. Among them, the key lies in designing the structure of the entire device and the corresponding method steps. At the device level, such as Figure 1 As shown, first design the substrate structure. Quartz glass is selected as the substrate, and the size can be selected as 2.5cm in diameter and 1mm in thickness. Then a gold film is plated on one side, and the thickness of the gold film is 50nm. Then PDMS is used as the packaging substrate, which is divided into two layers, and the upper and lower layers are designed to be ring-shaped. Among them, the lower layer is a ring with an inner ring diameter of 1cm, a thickness of 1mm, and an outer ring diameter of 4.5cm. The middle part is used as the cavitation cavity part to store drugs; the upper layer is a ring with an inner ring diameter of 2.5cm and an outer ring diameter of 4.5cm, which is used to embed quartz glass, combining the upper and lower parts together, and the gold-plated side of the quartz glass faces the cavitation cavity, thereby forming the main part of the device (the shape of this part of the PDMS can be changed according to the patient's skin structure and the shape of the glass patch). Because photoultrasound requires a material with plasmonics, gold was chosen as the material. UV spectrophotometry reveals a strong absorption peak around 530 nm in the visible light range. Quartz glass also has excellent light transmittance, making it suitable as a coating substrate. PDMS is very soft and skin-friendly, allowing it to adhere more closely to the skin when used as a chimeric material. A cavitation cavity with a diameter of 1 cm and a depth of 1 mm was created in the center to maximize the cavitation-induced drug release performance.

[0035] like Figure 2As shown, the laser emitted by a 532nm pulsed laser is designed by the present invention to be incident on a convex lens with three full reflectors to focus the light beam so that the spot diameter of the laser incident point is about 1mm, the duration of a single pulse laser is about 10ns, and the operating power of the laser is between 250mW and 300mW (to prevent excessive power from damaging the skin). By adjusting the angle of a single reflector, the pulsed laser can be moved on a one-dimensional line, and by adjusting the angles of two of the reflectors, the laser can be moved in a two-dimensional plane. If the height of the convex lens is further adjusted to adjust the focal point, the end of the light can be moved in three-dimensional space. In summary, this part of the design can make the incident point of the laser adjusted in three dimensions to achieve optimal device efficiency. This part of the optical path design concept can also be placed in a black box and fine-tuned using a motor system.

[0036] like Figure 3 As shown, the ultrasonic wave generated by the piezoelectric material in the general scheme is a contact method (circuit design is required). In the technical solution of the present application, based on the principle of photo-ultrasound effect, it is specifically a non-contact ultrasonic wave generation method (split type, the excitation source and the device can be separated), which uses the energy of light to excite the thermal effect inside the medium, thereby generating ultrasonic waves. Furthermore, ultrasonic waves are divided into low-frequency ultrasonic waves (0-20kHz), medium-frequency ultrasonic waves (20kHz-1MHz) and high-frequency ultrasonic waves (above 1MHz) according to the frequency. When the ultrasonic frequency reaches 80kHz or higher, the cavitation bubbles generated will become smaller and more numerous. Although these small cavitation bubbles have weak individual impact force, they can penetrate deeper into narrow gaps and holes, which is very consistent with the structure of human skin, and can achieve the best effect of accelerating the transdermal diffusion of drugs. In the technical solution of this application, an acoustic transducer is used, immersed in the liquid at a distance of about 10 mm from the laser incident point, without contact with the container wall, to collect the ultrasonic frequency and amplitude converted by the photoacoustic effect. After Fourier transform, it is measured that the ultrasonic frequency has the maximum intensity at 100 kHz, thereby maximizing the performance of the device.

[0037] Furthermore, most drugs that penetrate the skin barrier are small molecules. The technical solution of this application specifically contemplates the use of nicotinamide (NIA) as a sample drug. The collapse of cavitation bubbles generates strong pressure, which can temporarily change the permeability of the skin surface and increase the probability of transdermal transport of small molecule drugs. The feasibility and efficiency of the solution are verified by comparing the depth of NIA injection with the depth of free diffusion of NIA over the same time period. The penetration is observed using fluorescence microscopy and laser confocal microscopy. Furthermore, using agarose to simulate skin, the relationship between laser action time, laser power, and drug injection depth is measured.

[0038] In order to evaluate the efficacy of the photoacoustic conversion device as an ultrasound introduction device, the present application not only performs simulation on the simulation software, but also performs a penetration study on an in vitro pig model to evaluate the transport of NIA in the Franz diffusion cell. Under the conditions of free diffusion and photoacoustic ultrasound penetration (at 100 times the range, using a laser confocal microscope to shoot), the fluorescence intensity of the sample after photoacoustic ultrasound penetration is significantly greater than that of free diffusion. The average depth of the drug (fluorescence) after free diffusion is about 100 microns, and the average depth of the drug (fluorescence) after 5min photoacoustic ultrasound penetration is about 250 microns, and its penetration depth rate is about 2.5 times that of free diffusion. It can be seen that the technical solution of the present invention is the result of the intersection of optics, acoustics and medicine. It has the efficacy of ultrasound penetration and optical controllability, which can bring more precise control effects than other devices.

[0039] It should be noted that within the scope of protection defined in the claims of the present invention, the following embodiments can be combined and / or expanded or replaced in any logical way from the above specific implementation methods, such as disclosed technical principles, disclosed technical features or implicitly disclosed technical features.

[0040] Example 1

[0041] A non-invasive drug transdermal transport device based on photoacoustic effect, comprising:

[0042] a substrate, on which a film layer is plated;

[0043] The encapsulation substrate layer is divided into two layers, the upper and lower layers; both the upper and lower layers are designed in a ring shape, and the middle part of the lower layer is provided with a cavitation cavity for storing drugs; the upper layer is used to embed the substrate; the upper and lower layers are combined together, with the substrate coating side facing the cavitation cavity;

[0044] The excitation light source system is used to focus the light beam and adjust the incident point of the laser in three dimensions to achieve optimal device efficiency.

[0045] Example 2

[0046] Based on Example 1, the excitation light source system specifically includes: a light source, three total reflection mirrors and a convex lens; the light emitted by the light source is incident on a convex lens through the three total reflection mirrors to focus the light beam; adjusting the angle of a single reflection mirror can make the pulsed laser move on a one-dimensional line, and adjusting the angles of two of the reflection mirrors can make the laser move in a two-dimensional plane. If the height of the convex lens is further adjusted to adjust the focal point, the end of the light beam moves in three-dimensional space.

[0047] Example 3

[0048] Based on Example 2, a motor system is further included. The excitation light source system is placed in a black box and the motor system is used to fine-tune the position of the total reflection mirror.

[0049] Example 4

[0050] Based on Example 1, the substrate comprises quartz glass.

[0051] Example 5

[0052] Based on Example 4, the film layer includes a gold film.

[0053] Example 6

[0054] Based on Example 1, the encapsulation base layer includes a PDMS material encapsulation base layer; the shape of the PDMS material encapsulation base layer can be changed according to the patient's skin structure.

[0055] Example 7

[0056] A non-invasive transdermal drug delivery method based on photoacoustic effect, such as Figure 4 As shown, the following steps are included:

[0057] S1, using the photo-induced ultrasonic effect and ultrasonic cavitation effect, uses materials with plasmon effect as the substrate for photoacoustic energy conversion, and selects laser energy and wavelength to generate ultrasonic waves of a certain frequency;

[0058] S2, when the ultrasound reaches a certain threshold, cavitation bubbles are generated in the liquid environment. The bursting of the bubbles releases energy, which promotes the transdermal transport of drugs.

[0059] Example 8

[0060] On the basis of Example 7, in step S1, the ultrasonic wave of a certain frequency is specifically made to reach an ultrasonic wave frequency of 80 kHz or higher.

[0061] Example 9

[0062] On the basis of Example 7, the non-invasive drug transdermal transport device based on the photoacoustic effect described in any one of Examples 1 to 6 is used, and the operating power of the laser of the excitation light source system is between 250mW and 300mW.

[0063] Example 10

[0064] Based on Example 9, the laser includes a 532 nm pulse laser.

[0065] The above description is merely the technical principles and preferred embodiments used in the present invention. Those skilled in the art will appreciate that the present invention is not limited to the specific embodiments described herein. It is obvious that various changes, adjustments, and substitutions can be made by those skilled in the art without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in more detail through the above embodiments, the present invention is not limited to the above embodiments. Without departing from the principles and concepts of the present invention, it may also include more other equivalent embodiments, and the scope of the present invention is determined by the scope of the appended claims.

Claims

1. A non-invasive drug transdermal transport device based on photoacoustic effect, characterized in that: include: a substrate, on which a film layer is plated; The encapsulation substrate layer is divided into two layers, the upper and lower layers; both the upper and lower layers are designed in a ring shape, and the middle part of the lower layer is provided with a cavitation cavity for storing drugs; the upper layer is used to embed the substrate; the upper and lower layers are combined together, with the substrate coating side facing the cavitation cavity; The excitation light source system is used to focus the light beam and adjust the incident point of the laser in three dimensions to achieve optimal device efficiency.

2. The non-invasive drug transdermal transport device based on photoacoustic effect according to claim 1, characterized in that: The excitation light source system specifically includes: a light source, three total reflection mirrors and a convex lens; the light emitted by the light source is incident on a convex lens through the three total reflection mirrors to focus the light beam; adjusting the angle of a single reflection mirror can make the pulsed laser move on a one-dimensional line, and adjusting the angle of two of the reflection mirrors can make the laser move in a two-dimensional plane. If the height of the convex lens is further adjusted to adjust the focal point, the end of the light beam can move in three-dimensional space.

3. The non-invasive drug transdermal transport device based on photoacoustic effect according to claim 2, characterized in that: It also includes a motor system. The excitation light source system is placed in a black box and the motor system is used to fine-tune the position of the total reflection mirror.

4. The non-invasive drug transdermal transport device based on photoacoustic effect according to claim 1, characterized in that: The substrate comprises quartz glass.

5. The non-invasive drug transdermal transport device based on photoacoustic effect according to claim 4, characterized in that: The film layer includes a gold film.

6. The non-invasive drug transdermal transport device based on photoacoustic effect according to claim 1, characterized in that: The packaging base layer includes a PDMS material packaging base layer; the shape of the PDMS material packaging base layer can be changed according to the skin structure of the patient.

7. A non-invasive drug transdermal transport method based on photoacoustic effect, characterized in that: The steps include: S1, using the photo-induced ultrasonic effect and ultrasonic cavitation effect, uses materials with plasmon effect as the substrate for photoacoustic energy conversion, and selects laser energy and wavelength to generate ultrasonic waves of a certain frequency; S2, when the ultrasound reaches a certain threshold, cavitation bubbles are generated in the liquid environment. The bursting of the bubbles releases energy, which promotes the transdermal transport of drugs.

8. The non-invasive drug transdermal transport method based on photoacoustic effect according to claim 7, characterized in that: In step S1, the ultrasonic wave of a certain frequency is specifically made to have a frequency of 80 kHz or higher.

9. The non-invasive drug transdermal transport method based on photoacoustic effect according to claim 7, characterized in that: A non-invasive drug transdermal transport device based on photoacoustic effect according to any one of claims 1 to 6 is used, wherein the operating power of the laser of the excitation light source system is between 250mW and 300mW.

10. The non-invasive transdermal drug delivery method based on photoacoustic effect according to claim 9, characterized in that: The laser includes a 532 nm pulse laser.

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