Transdermal drug administration system, transdermal drug administration method, and transdermal drug administration device

Abstract

A transdermal drug administration system comprising: a first ultrasonic wave production means that emits first ultrasonic waves with a low frequency into skin, in order to cause peeling due to cavitation in the stratum corneum of the skin; and a second ultrasonic wave production means that produces an acoustic flow by emitting second ultrasonic waves with a higher frequency than that of the first ultrasonic waves, in order to cause a drug to penetrate under the corneum in which the peeling has occurred.

Description

Transdermal drug administration system, transdermal drug administration method, and transdermal drug administration device

[0001] The present disclosure relates to a transdermal drug administration system, a transdermal drug administration method, and a transdermal drug administration device that utilize ultrasound.

[0002] Due to their specificity, biopolymer drugs have attracted attention as drugs that enable treatment with high efficacy and few side effects. Oral administration and transdermal administration are considered to be minimally invasive methods for administering biopolymer drugs. In the case of oral administration, biopolymer drugs are highly hydrophilic and therefore cannot permeate cell membranes, making absorption from the digestive tract difficult, which limits the types of drugs that can be administered.

[0003] On the other hand, transdermal administration is a method of administering drugs through the skin. The stratum corneum, the outermost layer of the skin, acts as a barrier to protect the body from external foreign substances such as microorganisms and physicochemical stimuli, making it difficult to administer biopolymer drugs with large molecular weights of approximately 150 to several thousand kDa. That is, transdermal administration requires penetration of the stratum corneum, but application by topical administration can only penetrate the stratum corneum with extremely small molecular weights (e.g., 500 Da or less) (K. van der Maaden, W. Jiskoot & J. Bouwstra, "Microneedle technologies for (trans)dermal drug and vaccine delivery", J. Controlled Release, Vol. 161, pp. 645-655, 2012).

[0004] For these reasons, biopolymer drugs are currently administered directly subcutaneously via injection. This method is problematic because it is painful and can cause significant stress to the patient. Therefore, we focused on sonophoresis (ultrasound introduction), a minimally invasive needleless drug administration method that can administer large molecular weight biopolymer drugs. Sonophoresis uses ultrasound-induced cavitation to deliver large molecular weight substances, such as biopolymer drugs, deep into the body through the skin.Therefore, studies have been reported on administering drugs by irradiating low-frequency ultrasound, mainly in the kHz range (S. Mitragotri, D. Blankschtein & R. Langer, "Ultrasound-Mediated Transdermal Protein Delivery", Science, Vol. 269, pp. 850-853, 1995; S. Mitragotri, D. A. Edwards, D. Blankschtein & R. Langer, "A mechanistic study of ultrasonically-enhanced transdermal drug delivery", J. Pharm. Sci., Vol. 84, pp. 697-706, 1995; A. Tezel, A. Sens & S. Mitragotri, "Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy", J. Pharm. Sci., Vol. 91, pp. 444-453, 2001; A. Tezel, A. Sens, J. Tuchscherer & S. Mitragotri, "Frequency Dependence of Sonophoresis", Pharm. Res., Vol.18, pp.1694-1700, 2001; Boucaud A, Garrigue MA,et al., "Effect of sonication parameters on transdermal delivery of insulin to hair-less rats", J. Pharm. Sci., Vol.81, pp.113-119, 2002).

[0005] In addition, a technology has also been disclosed that attempts to administer or penetrate drugs into the skin using two types of sound waves. The technology described in JP-A-2017-501809 combines a magnetostrictive element and a piezoelectric element, with the magnetostrictive element being used to emit sound waves in the audible range. The technology described in WO 03 / 061753 A1 uses a single piezoelectric element to generate multiple vibration modes. In this case, low frequencies do not vibrate in the thickness direction of the skin, but rather in the out-of-plane direction, with amplitudes that vary significantly depending on the vibration position. Therefore, when low frequencies are irradiated, an out-of-plane vibration mode occurs, resulting in significant unevenness depending on the area. The technology described in JP-A-2008-515581 uses a phased array, but this method increases output by accumulating weak ultrasound.

[0006] In transdermal administration using ultrasound, the success of keratin ablation and subsequent drug injection depended on the action of randomly generated cavitation. Because the microjets induced by cavitation lack directionality and must be generated near the keratin, efficient keratin ablation was difficult. Furthermore, to deliver drugs into the skin through the ablated keratin, the drugs must reach the ablated area. However, active drug delivery to the ablated area has not been sufficiently studied, making efficient drug administration difficult.

[0007] Furthermore, although studies have been conducted on the frequency when using a single vibrator and on combining sonophoresis with penetration enhancers or nanocarriers, there has been little research to date on ultrasound irradiation methods using multiple vibrators, especially ultrasound irradiation techniques that use multiple vibrators to improve drug administration efficiency.

[0008] The present disclosure provides a transdermal drug administration system, a transdermal drug administration method, and a transdermal drug administration device that can efficiently administer even high molecular weight drugs to the skin using two types of ultrasound that have different effects on the skin.

[0009] (1) Transdermal drug administration system A transdermal drug administration system according to an embodiment of the present disclosure comprises a first ultrasonic wave generating means for irradiating the skin with a first low-frequency ultrasonic wave in order to cause cavitation-induced peeling in the stratum corneum of the skin, and a second ultrasonic wave generating means for generating acoustic streaming by irradiating a second ultrasonic wave having a higher frequency than the first ultrasonic wave in order to allow a drug to penetrate under the stratum corneum where the peeling has occurred.

[0010] The transdermal drug delivery system preferably further comprises a drug delivery means for delivering the drug to the surface of the skin.

[0011] It is desirable that the transdermal drug administration system further comprises a holding means for maintaining a distance between the second ultrasonic generating means and the skin of 0.1 to 10 mm.

[0012] In the transdermal drug administration system, it is desirable that the second ultrasonic wave be irradiated onto the skin for 1 second to 1 hour.

[0013] In the transdermal drug delivery system, the frequency of the second ultrasonic wave is preferably 1.5 to 50 MHz.

[0014] With the above configuration, the transdermal drug administration system can suitably administer drugs with a molecular weight of 5 to 150 kDa.

[0015] (2) Transdermal Drug Administration Method The transdermal drug administration method of an embodiment of the present disclosure includes a cavitation step of irradiating the skin with a first low-frequency ultrasonic wave to cause cavitation-induced peeling in the stratum corneum of the skin, a drug application step of applying a drug under the peeled stratum corneum, and a drug penetration step of generating acoustic streaming by irradiating the peeled stratum corneum with a second ultrasonic wave having a higher frequency than the first ultrasonic wave.

[0016] It is desirable to maintain the distance between the second ultrasonic generator that generates the acoustic streaming and the skin at 0.1 to 10 mm.

[0017] In the transdermal drug administration method, it is desirable that the second ultrasonic wave be irradiated onto the skin for 1 second to 1 hour.

[0018] In the transdermal drug administration method, the frequency of the second ultrasonic wave is preferably 1.5 to 50 MHz.

[0019] With the above-described configuration, the transdermal drug administration method can suitably administer the drug having a molecular weight of 5 to 150 kDa.

[0020] (3) Transdermal Drug Administration Device A transdermal drug administration device according to an embodiment of the present disclosure includes a first ultrasonic generator that irradiates the skin with a first low-frequency ultrasonic wave to cause cavitation-induced peeling in the stratum corneum of the skin, and a second ultrasonic generator that irradiates a second ultrasonic wave that has a higher frequency than the first ultrasonic wave to generate acoustic streaming so as to allow a drug to penetrate under the stratum corneum where the peeling has occurred.

[0021] The transdermal drug administration device preferably further comprises a drug supplier for supplying the drug to the surface of the skin.

[0022] It is desirable that the transdermal drug administration device further comprises a second holder for maintaining a distance of 0.1 to 10 mm between the second ultrasonic generator and the skin.

[0023] In the transdermal drug administration device, it is desirable that the second ultrasonic wave be irradiated onto the skin for a period of 1 second to 1 hour.

[0024] In the transdermal drug administration device, the frequency of the second ultrasonic wave is preferably 1.5 to 50 MHz.

[0025] With the above-described configuration, the transdermal drug administration device can suitably administer drugs having a molecular weight of 5 to 150 kDa.

[0026] The present disclosure provides a transdermal drug administration device and a transdermal drug administration method that can efficiently administer even high molecular weight drugs to the skin by using two types of ultrasound that have different effects on the skin.

[0027] 8A is a conceptual diagram of a transdermal administration system of a first embodiment. FIG. 8B is a schematic diagram of a first ultrasonic generator as a first ultrasonic generating means. FIG. 8C is a schematic diagram of a second ultrasonic generator as a second ultrasonic generating means. FIG. 8D is a schematic diagram of a modified example of a second ultrasonic generator as a second ultrasonic generating means. FIG. 8E is a schematic diagram of a state in which peeling due to cavitation has occurred in the stratum corneum of the skin. FIG. 8F is a schematic diagram of a state in which acoustic streaming is applied to the stratum corneum of the skin. FIG. 8G is a schematic diagram of a transdermal drug administration device of a second embodiment. FIG. 8H is a schematic diagram of a modified example of a transdermal drug administration device of the second embodiment. FIG. 8I is a graph showing the relationship between the distance from the acoustic source and the flow velocity in the second ultrasonic generator. FIG. 8I is a graph showing the relationship between the distance from the acoustic source and the flow velocity in the second ultrasonic generator for each second frequency. The graph of FIG. 8A is an enlarged view of the vicinity of the vertical axis. FIG. 8I is a graph showing the results of measuring acoustic streaming at two different frequencies. FIG. 8J is a graph showing the results of examining ultrasound generation conditions using a drug administration model. FIG. 8I is a confocal microscope photograph of a frozen section of skin used in the Control drug model shown in the Examples. FIG. 8I is a graph showing the relationship between the distance from the acoustic source and the flow velocity in the second ultrasonic generator for each second frequency. 1 shows confocal micrographs of frozen sections of skin used in the drug model of Exp. 1. 2 shows confocal micrographs of frozen sections of skin used in the drug model of Exp. 3 shown in the Examples.

[0028] Hereinafter, embodiments of the present disclosure will be described with reference to the drawings. Common reference numerals in each drawing indicate the same parts unless otherwise specified. Furthermore, each member and each part shown in each drawing is merely a schematic drawing, and does not necessarily accurately reflect the size and positional relationship of an actual device. In this specification, when a numerical range is expressed, for example, as "m to n," it means "greater than or equal to m and less than or equal to n," unless otherwise specified.

[0029] (1) Transdermal Drug Administration System, Transdermal Drug Administration Method, and Transdermal Drug Administration Device (1-1) First Embodiment A transdermal drug administration system 1 of the first embodiment includes a first ultrasonic wave generating means 2 and a second ultrasonic wave generating means 4, as shown in the schematic diagram of Fig. 1. The first ultrasonic wave generating means 2 can be any means that generates cavitation in the liquid 70 and exfoliates the stratum corneum, and among these, a first ultrasonic wave generator 20 including a Langevin type vibrator that generates longitudinal vibrations as shown in Fig. 2 is preferred in order to generate cavitation efficiently.

[0030] The transdermal drug administration system 1 of this embodiment includes, for example, a first ultrasonic wave generating means 2 having a first ultrasonic generator 20 as schematically shown in Fig. 2 and a second ultrasonic wave generating means 4 having a second ultrasonic generator 40 as schematically shown in Fig. 3. The first ultrasonic wave generating means 2 irradiates the skin 60 with a first ultrasonic wave of a low frequency to generate a cavitation-induced peeling 63 in the stratum corneum 61 of the skin 60. The second ultrasonic wave generating means 4 irradiates the skin 60 with a second ultrasonic wave of a higher frequency than the first ultrasonic wave to generate acoustic streaming 100 in order to efficiently penetrate the drug 80 into the substratum corneum 62 where the peeling 63 has occurred. Note that, in the present disclosure, "acoustic streaming" refers to a direct current flow of fluid elements that occurs when a powerful ultrasonic wave is irradiated into a fluid.

[0031] Furthermore, the transdermal drug administration system 1 of the present embodiment described above implements a transdermal drug administration method including a cavitation step of irradiating the skin 60 with a first low-frequency ultrasonic wave to generate cavitation-induced peeling 63 in the stratum corneum 61 of the skin 60, a drug supply step of supplying the drug 80 to the substratum corneum 62, and a drug penetration step of irradiating the stratum corneum 61 where the peeling 63 has occurred with a second ultrasonic wave of a higher frequency than the first ultrasonic wave to generate acoustic streaming 100. The first ultrasonic generator 20 irradiates the skin 60 with a first low-frequency ultrasonic wave to generate cavitation-induced peeling 63 in the stratum corneum 61 of the skin 60 (see FIG. 4 ). The second ultrasonic generator 40 irradiates the skin 60 with a second ultrasonic wave of a higher frequency than the first ultrasonic wave to generate acoustic streaming 100 to penetrate the stratum corneum 61 where the peeling 63 has occurred.

[0032] More specifically, as shown in FIG. 2 , the first ultrasonic generator 20 serving as the first ultrasonic generating means 2 has a first ultrasonic generating element 21 attached to the tip of a fixed shaft 11, and a first holder 30 attached to maintain a distance between the skin 60 and the first ultrasonic generating element 21. The first holder 30 is made of a metal such as stainless steel and is formed to match the shape of the first ultrasonic generating element 21 (for example, if the first ultrasonic generating element 21 is a cylindrical piezoelectric element, the first holder 30 is formed to have the same outer diameter as the first ultrasonic generating element 21). The cavitation step of the transdermal drug administration method described above is performed by the first ultrasonic generator 20 serving as the first ultrasonic generating means 2. The first ultrasonic generating element 21 can be formed of a piezoelectric material such as lead zirconate titanate (PZT). While FIG. 2 illustrates a Langevin-type transducer, this is not limiting. Preferably, the distance between the first ultrasonic generator 20 and the skin is 0 to 100 mm, the frequency of the generated first ultrasonic waves is 20 to 500 kHz, and the exposure time to the skin is 1 second to 1 hour.

[0033] On the other hand, as shown in FIG. 3 , the second ultrasonic generator 40 serving as the second ultrasonic generating means 4 has a configuration in which a second ultrasonic generating element 41 is attached to the tip of a fixed shaft 11, and a second holder 50 is attached as a holding means for maintaining a distance of 0.1 to 10 mm between the skin 60 and the second ultrasonic generating element 41. The second holder 50 is formed, for example, from silicone resin, into a short cylindrical shape with a through-hole 51 formed in the center. The inner diameter of the upper portion of the through-hole 51 is larger than the inner diameter of the lower portion, and the second ultrasonic generator 40 is held in a large-diameter portion 52 above the through-hole 51 by a step created by this difference in inner diameter. The height of a small-diameter portion 53 below the through-hole 51 corresponds to the distance between the skin 60 and the second ultrasonic generator 40. The second ultrasonic wave generating element 41 is preferably composed of a piezoelectric element (or piezo element) made of an inorganic material such as PZT, lead magnesium niobate titanate (PMN-PT), relaxor piezoelectric single crystal (PIN-PMN-PT), ceramics containing a solid solution of barium titanate and bismuth ferrite, or an organic material such as polyvinylidene fluoride (PVDF). The frequency of the second ultrasonic wave generated thereby is 0.5 to 50 MHz. The irradiation time of the second ultrasonic wave to the skin is 1 second to 1 hour. The second ultrasonic wave may be repeatedly irradiated to the skin, and the repeated irradiations may be for the same or different durations. The drug penetration step of the transdermal drug administration method is carried out by the second ultrasonic generator 40 as the second ultrasonic wave generating means 4.

[0034] As shown in FIG. 3A , the second ultrasonic generator 40 of this embodiment further includes a drug supplier 15 as a drug supplying means for supplying drug 80 to the surface of skin 60. This drug supplier 15 can be configured, for example, as a liquid supplying device having a nozzle capable of automatically supplying a predetermined amount of liquid 70 containing drug 80. The drug supplier 15 performs the drug supplying step in the transdermal drug administration method. This drug supplying step may be performed either before or after the cavitation step. Furthermore, this drug supplying step can also be performed without using the drug supplier 15, for example, by manually dripping a predetermined amount of liquid onto the surface of skin 60 using a pipette.

[0035] 3B , second holder 50 of second ultrasonic generator 40 of the present embodiment may be provided with syringe attachment unit 54 to which a syringe pre-filled with a drug (e.g., a pre-filled syringe) can be attached as drug supplier 15. Syringe attachment unit 54 is an opening provided on the top surface of second holder 50, and communicates with small diameter portion 53 of through-hole 51 via drug supply path 55. That is, by attaching drug supplier 15 to syringe attachment unit 54 and injecting the filled drug 80, drug 80 is supplied to the surface of skin 60.

[0036] Fig. 4 is a schematic diagram showing a state in which cavitation-induced peeling 63 has occurred in the stratum corneum 61 of skin 60. As shown in Fig. 2, when the first ultrasonic wave is irradiated, liquid 70 is interposed between the tip of a metallic first holder 30 attached below the first ultrasonic generator 20 and the skin 60, and liquid 70 dropped onto the skin 60 is interposed between the first holder 30 and the skin 60. Then, as shown in Fig. 4, bubbles 90 are generated in the liquid 70 by the first ultrasonic wave generated from the first ultrasonic generator 20, and shock waves generated by the bursting of these bubbles 90 cause fine peeling 63 in the stratum corneum 61 (cavitation).

[0037] Figure 5 is a schematic diagram of the state in which acoustic streaming 100 is applied to the stratum corneum 61 of skin 60. As shown in Figure 3, small-diameter portion 53 of through-hole 51 of second holder 50 is filled with liquid 70 containing drug 80, thereby applying drug 80 to skin 60. In this state, acoustic streaming 100 generated by the second ultrasonic wave expands a separation 63 (see Figure 4) in stratum corneum 61 caused by cavitation, and drug 80 penetrates through this expanded separation 63 into substratum corneum 62. In this way, by applying acoustic streaming 100 to stratum corneum 61 of skin 60 in addition to the generation of separation 63 caused by cavitation, it becomes possible to transdermally administer drug 80 with a high molecular weight (specifically, 5 to 150 kDa), which is normally difficult to administer transdermally.

[0038] 6 is a schematic diagram of a transdermal drug administration device 10 according to a second embodiment. The transdermal drug administration device 10 includes a first ultrasonic generator 20 that irradiates the skin with a first ultrasonic wave of a low frequency to generate cavitation-induced peeling 63 in the stratum corneum 61 of the skin, and a second ultrasonic generator 40 that irradiates a second ultrasonic wave of a higher frequency than the first ultrasonic wave to generate acoustic streaming 100 to allow drug 80 to penetrate into the substratum corneum 62 where the peeling 63 has occurred.

[0039] That is, a first ultrasonic generating element 21 serving as a first ultrasonic generator 20 is attached to the tip of the fixed shaft 11, and a first holder 30 is attached to maintain a distance between the skin 60 and the first ultrasonic generating element 21. The first ultrasonic generating element 21 can be formed of a piezoelectric material such as lead zirconate titanate (PZT). While a Langevin type transducer is illustrated in FIG. 6, this is not limiting. Furthermore, it is preferable that the distance between the first ultrasonic generator 20 and the skin is 0 to 100 mm, the frequency of the generated first ultrasonic waves is 20 to 500 kHz, and the irradiation time to the skin is 1 second to 1 hour.

[0040] That is, when the frequency of the first ultrasonic wave is less than 20 kHz, the low frequency results in insufficient particle acceleration, and cavitation is not stably formed, making it impossible to sufficiently destroy the stratum corneum 61. On the other hand, when the frequency of the first ultrasonic wave exceeds 500 kHz, the size of the generated cavitation falls below 1 μm, which is insufficient to perforate the stratum corneum 61, which is approximately 20 μm thick, and the drug cannot pass through the stratum corneum. Therefore, in order to sufficiently destroy the stratum corneum 61 with a sufficient size, the frequency of the first ultrasonic wave is preferably 20 to 500 kHz, as described above.

[0041] A second ultrasonic generator 40 is interposed between the tip of the first holder 30 and the skin 60. The second ultrasonic generator 40 includes a short cylindrical second holder 50 having a predetermined height and a second ultrasonic generating element 41 held within the second holder 50. The second ultrasonic generating element 41 has a structure in which a piezoelectric element (or piezo element) made of an inorganic material such as PZT, PMN-PT, PIN-PMN-PT, or ceramics containing a solid solution of barium titanate and bismuth ferrite, or an organic material such as PVDF, is processed into a spherical shape. This structure allows the acoustic streaming 100 to converge toward the center. The frequency of the second ultrasonic waves generated by the second ultrasonic generating element 41 is 1.5 to 50 MHz. The time period for irradiating the skin with the second ultrasonic waves is 1 second to 1 hour. The second ultrasonic waves may be irradiated repeatedly to the skin, and the repeated irradiations may be for the same or different durations.

[0042] Furthermore, transdermal drug administration device 10 of this embodiment is also provided with drug supplier 15, which penetrates fixed shaft 11, first ultrasonic generating element 21, and first holder 30 and opens into the internal space of second ultrasonic generating element 41. With transdermal drug administration device 10 placed on skin 60, liquid 70 containing drug 80 is supplied onto skin 60 from drug supplier 15. In this state, first ultrasonic waves are irradiated onto skin 60 from first ultrasonic generating element 21, which generates bubbles 90 in liquid 70. Shock waves generated by the bursting of bubbles 90 cause microscopic abrasions 63 in stratum corneum 61 (cavitation).

[0043] 6B , the second holder 50 of the second ultrasonic generator 40 of the present embodiment may be provided with a syringe attachment unit 54 to which a syringe pre-filled with a drug (e.g., a pre-filled syringe) can be attached as the drug supplier 15. The syringe attachment unit 54 is an opening provided on the top surface of the second holder 50, and communicates with the internal space of the second ultrasonic generating element 41 via a drug supply path 55. That is, by attaching the drug supplier 15 to the syringe attachment unit 54 and injecting the loaded drug 80, the drug 80 is supplied to the surface of the skin 60.

[0044] In transdermal drug administration device 10 of this embodiment, second ultrasonic waves can be irradiated from second ultrasonic generating element 41 to skin 60 simultaneously with the irradiation of the first ultrasonic waves. That is, acoustic streaming 100 generated by the second ultrasonic waves expands peeling 63 in stratum corneum 61 caused by cavitation, and drug 80 penetrates into substratum corneum 62 through this expanded peeling 63. Note that skin 60 may be irradiated with the first ultrasonic waves before the second ultrasonic waves.

[0045] (2) Conditions for Generating Acoustic Streaming The irradiation distance and frequency for suitably generating acoustic streaming in second ultrasonic generator 40 as the second ultrasonic generating means will be considered as follows.

[0046] (2-1) Radiation distance The velocity of acoustic streaming (u(s)) generated from an acoustic source with a finite area １ , s ２ The function of ) is calculated by the following formula (1) (Michael B. Dentry, Leslie Y. Yeo, James R. Friend, "Frequency effects on the scale and behavior of acoustic streaming", Phys. Rew. E, 013203, 2019). In the formula (1), X is the component in the propagation direction of the ultrasound, and s １ and s ２ are the components perpendicular to the propagation direction.

[0047]

[0048] In the above formula (1), the flow velocity u(s １ , s ２ ) is s １ = 0, s ２ It is known that the maximum flow velocity occurs when u(0,0) = 0. That is, the function of the maximum flow velocity u(0,0) is expressed by the following equation (2).

[0049]

[0050] Here, f(X) in the above formula (2) is a function related to momentum flux, and S ｉis the width of the acoustic streaming in a sound source of finite area. f(X) is expressed by the following equation (3).

[0051]

[0052] In the above formula (3), ρ is the density of water (ρ = 1,000 kg / m ３ ), c is the speed of sound in water (c = 1,500 m / s), P is acoustic power, and β is the attenuation coefficient of acoustic power. β is expressed by the following equation (4).

[0053] The b in the above formula (4) is expressed by the following formula (5).

[0054]

[0055] In the above formula (5), μ is the viscosity coefficient (μ=1.0×10 ３ In addition, μ' is the bulk viscosity coefficient, and can be approximated as μ' = 0 by incompressibility approximation. Furthermore, ω in the above formula (4) is the angular frequency, and when the irradiation frequency is 1.97 MHz, ω = 1.97 × 2π × 10 ６ rad / s. Furthermore, P in the above formula (3) is expressed by the following formula (6).

[0056]

[0057] I in the above formula (6) ＳＰＴＡ is the acoustic intensity, and from the viewpoint of ensuring safety in the living body, I ＳＰＴＡ = 720 mW / cm ２ In addition, D is the area of ​​the irradiation surface. In this embodiment, the diameter of the irradiation surface is 1.5 cm, so D is D=0.75 ２ ×π cm ２ This becomes:

[0058] S in the formula (2) ｉ is expressed by the following equation (7). In the above formula (7), S is the width of the acoustic streaming at the point sound source. ｉ is the distance from the center of the sound source, and in this embodiment, A ｉ = 7.5 mm. S is expressed by the following formula (8).

[0059] Here, α in the above equation (8) is a constant that determines the width of the acoustic streaming, and can be determined by a constant k calculated from the angle of the acoustic streaming from the X-axis. The constant k is calculated as k = tan φ / 2.15. In this embodiment, φ = 10°, so k = 0.082.

[0060] Here, the set of solutions of the following equation (9) showing the relationship between the constant k and the constant α is shown in Table 1 below.

[0061]

[0062]

[0063] In Table 1, the constant α corresponding to k=0.09, which is closest to k=0.082, is α=0.102. ｉ By substituting α and σ into the above equations (7) and (8), S1 and S2 in the above equation (2) are expressed by the following equation (10).

[0064]

[0065] Combining the above formulas (2) to (9), the flow velocity u(0,0) in formula (2) is given by the following formula (11): Note that the unit of the variable X is mm.

[0066]

[0067] The numerical values ​​in the above formula (11) can be rearranged as follows. Note that "^" is the symbol representing exponentiation. u(0,0)=100e{54.0(1-1 / e^ 0.0605X )}^ (1 / 2) / (0.102X+7.5)

[0068] Equation (11) above can be expressed as a graph shown in FIG. 7 , with the vertical axis representing flow velocity u (mm / s) and the horizontal axis representing distance X (mm). This graph reveals that the flow velocity is small near the acoustic source (X = 0), increases with distance, and then decreases after reaching a maximum. Here, when the distance X from the acoustic source to the skin is 1 mm, the flow velocity u is calculated to be approximately 60 mm / s by substituting X = 1 into equation (11). From this graph, the maximum irradiation distance at which a flow velocity of 60 mm / s can be ensured can be calculated as 250 mm. Furthermore, the irradiation distance of the ultrasonic waves that generate acoustic streaming must be at least one wavelength away from the irradiated surface (i.e., the surface of the skin). Since the wavelength of the ultrasonic waves emitted from the piezoelectric element used in this embodiment is 0.76 mm, the minimum irradiation distance was set to 1 mm. Based on the above, in this embodiment, the irradiation distance of the second ultrasonic generator 40 is set to 1 mm or more and 250 mm or less.

[0069] (2-2) Frequency Acoustic streaming is generally said to occur clearly at frequencies above the MHz range. Furthermore, as the frequency increases, the distance over which the maximum flow velocity is reached becomes shorter, but the flow velocity decreases significantly. Therefore, if the frequency is set too high, a stable flow velocity cannot be ensured. Therefore, 120 MHz, which is the frequency at which a stable flow velocity can be ensured, is set as the maximum frequency. Furthermore, 0.5 MHz is set as the minimum frequency at which acoustic streaming occurs. For these reasons, in this embodiment, the frequency radiated by the second ultrasonic generator 40 is set to 0.5 MHz or higher and 120 MHz or lower, preferably 1.5 MHz or higher and 50 MHz or lower.

[0070] Fig. 8A is a graph showing the relationship between the distance from the acoustic source of the second ultrasonic generator and the flow velocity for each second frequency. Fig. 8B is a graph showing an enlarged view of the vertical axis of Fig. 8A . Figs. 8A and 8B show the relationship between the distance (mm) from the irradiation source and the flow velocity (mm / s) for second frequencies of 0.5 MHz (thin solid line), 1.5 MHz (thick solid line), 50 MHz (dashed line), and 120 MHz (dotted line). Note that in Figs. 8A and 8B , the dashed curves and the dotted curves are nearly identical.

[0071] 8A and 8B show that the flow velocity is maximized at the peak of the curve corresponding to each second frequency, and therefore, the preferred irradiation source is located near the distance corresponding to that peak. That is, when the second frequency is 0.5 MHz, the irradiation distance is preferably 25 to 135 mm. Furthermore, when the second frequency is 1.5 MHz, the irradiation distance is preferably 2 to 250 mm. Furthermore, when the second frequency is 50 MHz and 120 MHz, the irradiation distance is preferably 0.1 to 250 mm. When the second frequency is irradiated under these conditions, the irradiation distance can be maintained at a distance of at least one wavelength, and an acoustic streaming velocity of 60 mm / s can be maintained. In particular, when the second frequency is 50 MHz and 120 MHz, as shown in FIG. 8B, the acoustic streaming velocity exceeds 60 mm / s when the distance from the irradiation source is 0.1 mm.

[0072] Figure 9 is a graph showing the results of measuring the relationship between the distance from the transducer as an acoustic source and the flow velocity in the frequency bands around 2 MHz and 7 MHz. For irradiation of frequencies around 2 MHz, a piezoelectric element (PZT-Pb(ZR.Ti)O ３ For irradiation of frequencies around 7 MHz, lithium niobate with a resonance frequency of 6.46 MHz was used.

[0073] Specifically, ultrapure water was stored in a plastic container, and Styrofoam beads (refill beads, φ0.5 mm) were floated on the water surface. Acoustic streaming generated by ultrasound waves of each frequency band was then passed through the water. The resulting image was captured using a high-speed camera at a resolution of 1280 x 800 and a frame rate of 1000 fps. The coordinates of the Styrofoam beads were then read from the video and divided by the number of frames required for a 1 mm movement to calculate the average flow velocity. The power used for each measurement was 5±0.05 W. In each case, the measurement was repeated 10 times, and the average value and standard deviation were plotted on a graph.

[0074] 7 and 8, which show the simulation results, it can be seen that the acoustic streaming velocity attenuates significantly as the distance from the transducer increases. Therefore, taking into consideration that the drug to be supplied may actually have a higher viscosity than the ultrapure water used in the experiment, the distance between the second ultrasonic generating means and the skin is preferably 0.1 mm to 25 mm, and more preferably 0.1 mm to 10 mm.

[0075] In addition, when an expensive drug is used, the longer the irradiation distance, the greater the amount of drug used, resulting in increased costs. Therefore, from the viewpoint of cost-effectiveness, the distance between the second ultrasonic generating means and the skin is preferably 0.1 mm or more and 5 mm or less, and more preferably 0.1 mm or more and 2 mm or less.

[0076] 9 also confirmed that the higher the frequency of the second ultrasonic wave generating means, the shorter the distance at which acoustic streaming reaches its maximum flow velocity. Therefore, in order to shorten the distance between the second ultrasonic wave generating means and the skin, it is preferable to use a higher frequency in the second ultrasonic wave generating means. Additionally, the higher the frequency, the shorter the time required to reach the maximum flow velocity, which means that the drug can be delivered to the dermis more efficiently. Therefore, from the viewpoint of shortening the drug administration time and, ultimately, the time required for the subject to be restrained, it is preferable to use a second ultrasonic wave generating means with a higher frequency.

[0077] From the simulation results shown in FIGS. 7 and 8, the frequency of the second ultrasonic generator 40 is preferably set to 1.5 MHz or more and 50 MHz or less as the acoustic streaming generation condition. However, in consideration of the above-mentioned actual measurement results and the viewpoints of the amount of drug used and shortening the administration time, a frequency of 5 MHz or more and 50 MHz or less is preferable, and furthermore, from the viewpoint of ease of obtaining second ultrasonic generating elements, a frequency of 5 MHz or more and 20 MHz or less is even more preferable.

[0078] Below, we investigated whether transdermal administration of a biopolymer drug with a molecular weight of several thousand Da to 150 kDa was possible using the transdermal delivery system of the present disclosure, using a model in which the drug was administered to pigskin, a substance that resembles human skin. Ovalbumin (OVA), with a molecular weight of approximately 45 kDa, was used as the drug model. To quantify the subcutaneous dose of this drug model, OVA was pre-labeled with Cy5 (Cy5 NHS ester, Lumiprobe), a dye-labeled carboxylic acid. The excitation wavelength of Cy5 is 646 nm, and the fluorescence wavelength is 662 nm. Cy5-labeled OVA, the drug model, was dissolved in phosphate-buffered saline (PBS) to a final concentration of 3 mg / mL.

[0079] A pigskin obtained from a slaughterhouse was stretched on a flat surface, and 50 μL of the drug model was dropped onto it as a drug supply step. Then, the first and second ultrasonic waves were irradiated.

[0080] The first ultrasonic waves were irradiated using a first ultrasonic generator 20 as shown in Fig. 2 as first ultrasonic wave generating means. A Langevin transducer (HEC-1540P2BF, Honda Electronics Co., Ltd.) with a resonance frequency of 43.8 kHz was used as the first ultrasonic wave generating element 21. The diameter of the tip of the first holder 30 was 1.5 cm, the distance between the tip and the skin 60 was 1 mm, and the distance between the first ultrasonic generator 20 and the skin 60 was 0.5 mm.

[0081] The second ultrasonic waves were irradiated using a second ultrasonic generator 40 as shown in Fig. 3, which served as second ultrasonic wave generating means. A piezoelectric element (PZT-Pb(ZR.Ti) type (C-213), Fuji Ceramics) with a frequency of 1.97 MHz was used as the second ultrasonic wave generating element 41. The diameter of the tip of the second ultrasonic generator 40 was 1.5 cm, and the distance between the second ultrasonic generator 40 and the skin 60 was 1 mm.

[0082] The ultrasonic irradiation conditions were as follows. That is, in Control, the solution was dropped onto the skin, spread, and left for 10 minutes without irradiation with ultrasonic waves. In Exp. 1, the first ultrasonic wave (43.8 kHz) was irradiated for 10 minutes, but the second ultrasonic wave (1.97 MHz) was not irradiated. In Exp. 2, the second ultrasonic wave was irradiated for 10 minutes, but the first ultrasonic wave was not irradiated. In Exp. 3, the first ultrasonic wave was irradiated for 5 minutes, followed by the second ultrasonic wave for 5 minutes. In Exp. 4, the second ultrasonic wave was irradiated for 5 minutes, followed by the first ultrasonic wave for 5 minutes. The measured current for the first ultrasonic wave was 102±3 mA, and the measured current for the second ultrasonic wave was 730±10 mA. In each case, the measurement was repeated three times.

[0083] In each of the above cases, after application of the drug model, the drug model remaining on the skin was washed off with PBS, the liquid was gently wiped off, and the surface was allowed to dry. In this state, ultraviolet light with an excitation wavelength of 646 nm was irradiated, and the fluorescence intensity at a fluorescence wavelength of 662 nm emitted by Cy5 absorbed into the skin was measured using a spectrofluorometer. The results are shown in Figure 10. Each bar in Figure 10 is the average of three measurements.

[0084] As shown in Figure 10, the Control, in which no ultrasound was applied to the skin, had the lowest fluorescence intensity, indicating poor absorption of the drug into the skin. In the remaining Exp. 1 to Exp. 4, in which at least one of the first and second ultrasound waves was applied to the skin, the measured fluorescence intensity was at least twice that of the Control, indicating that ultrasound promoted absorption of the drug into the skin. Of these, the highest fluorescence intensity was observed in Exp. 3, in which a low-frequency (43.8 kHz) first ultrasound wave was applied first, followed by a high-frequency (1.97 MHz) second ultrasound wave.

[0085] Here, the fluorescence intensity in Exp. 4, in which the second ultrasonic wave was first irradiated followed by the first ultrasonic wave, was almost the same as the fluorescence intensity in Exp. 1, in which only the first ultrasonic wave was irradiated, suggesting that the second ultrasonic wave irradiated first did not contribute much to the uptake of the drug into the skin.

[0086] Figures 11A, 11B, and 11C are photographs of frozen sections of skin used in the drug models described above (Control, Exp. 1, and Exp. 3), taken with a confocal microscope at an excitation wavelength of 640 nm. In each figure, the dashed line indicates the stratum corneum, and the area below the dashed line corresponds to the substratum corneum. In the Control model, in which Cy5-labeled OVA was applied to the skin without ultrasound irradiation, no excitation light was observed beneath the stratum corneum, indicating that OVA was not absorbed beneath the stratum corneum (Figure 11A). In Exp. 1, in which Cy5-labeled OVA was applied to the skin and then only the first ultrasound was applied, excitation light was observed beneath the stratum corneum (Figure 11B). In Exp. 3, in which both the first and second ultrasounds were applied, even more excitation light was observed beneath the stratum corneum (Figure 11C). These results indicate that low-frequency acoustic streaming of the skin promotes the absorption of ovalbumin beneath the stratum corneum, but that the application of high-frequency acoustic streaming in addition to low-frequency acoustic streaming allows even more ovalbumin to be absorbed deeper beneath the stratum corneum. These results are consistent with the results shown in the graph in Figure 10.

[0087] From the above results, it was inferred that by irradiating the first ultrasonic wave, the stratum corneum is peeled off by the shock waves generated when bubbles generated by cavitation burst on the skin (see Figure 4), but this is then greatly expanded by the acoustic streaming generated by the second ultrasonic wave that is irradiated next (see Figure 5), making it easier for the drug to penetrate into the dermis.

[0088] The transdermal drug administration system, transdermal drug administration method and device, and transdermal drug administration device of the present invention enable efficient administration of drugs through the skin. The present invention can also be used appropriately in various regions and organs where epithelial cells are formed in biological tissues other than the skin. Specifically, the present invention can be applied to organs with tubular structures, such as the esophagus, stomach, and large intestine, which can be observed with upper and lower endoscopy; the bronchi and lungs, which can be observed with a bronchoscope; and the aorta and coronary arteries, which can be observed with a vascular endoscope. Furthermore, in various organs in the abdominal cavity, such as the stomach, large intestine, liver, pancreas, gallbladder, kidneys, prostate, uterus, and bladder, which can be observed with a laparoscope, the required drug can be efficiently administered by adapting the first and second ultrasonic generating means to the thickness and shape of the epithelial cells of the target organ.

Claims

1. A transdermal drug administration system comprising: a first ultrasound generating means for irradiating the skin with a first low frequency ultrasound to cause cavitation-induced peeling of the stratum corneum of the skin; a second ultrasound generating means for generating acoustic streaming by irradiating a second ultrasound of a higher frequency than the first ultrasound to allow a drug to penetrate under the stratum corneum where the peeling has occurred; and a drug supplying means for supplying the drug to the surface of the skin.

2. A transdermal drug administration system as described in claim 1, further comprising a holding means for keeping the distance between said second ultrasonic generating means and the skin at 0.1 to 10 mm.

3. The transdermal drug administration system of claim 2, wherein the second ultrasonic wave is irradiated onto the skin for a period of time ranging from 1 second to 1 hour.

4. The transdermal drug delivery system of claim 3, wherein the frequency of the second ultrasonic wave is 1.5 to 50 MHz.

5. The transdermal drug delivery system of claim 1, wherein the molecular weight of the drug is 5 to 150 kDa.

6. A method for transdermal drug administration comprising: a cavitation step of irradiating the skin with a first low-frequency ultrasound to cause cavitation-induced peeling of the stratum corneum of the skin; a drug supply step of supplying a drug to the stratum corneum; and a drug penetration step of generating acoustic streaming by irradiating a second ultrasound having a higher frequency than the first ultrasound under the stratum corneum where the peeling has occurred.

7. The method for transdermal drug administration according to claim 6, wherein the distance between the second ultrasonic generator that generates the acoustic streaming and the skin is kept at 0.1 to 10 mm.

8. The method for transdermal drug administration according to claim 7, wherein the second ultrasonic wave is irradiated onto the skin for a period of time ranging from 1 second to 1 hour.

9. The method of transdermal drug administration according to claim 8, wherein the frequency of the second ultrasonic wave is 1.5 to 50 MHz.

10. A method for transdermal drug administration described in any one of claims 6 to 9, wherein the molecular weight of the drug is 5 to 150 kDa.

11. A transdermal drug administration device comprising: a first ultrasonic generator that irradiates the skin with a first low-frequency ultrasonic wave to cause cavitation-induced peeling of the stratum corneum of the skin; a second ultrasonic generator that generates acoustic streaming by irradiating a second ultrasonic wave of a higher frequency than the first ultrasonic wave to allow a drug to penetrate under the stratum corneum where the peeling has occurred; and a drug supplier that supplies the drug to the surface of the skin.

12. A transdermal drug administration device according to claim 11, further comprising a second holder for maintaining a distance between the second ultrasonic generator and the skin of 0.1 to 10 mm.

13. The transdermal drug administration device according to claim 12, wherein the second ultrasonic wave is irradiated onto the skin for a period of time ranging from 1 second to 1 hour.

14. The transdermal drug administration device according to claim 13, wherein the frequency of the second ultrasonic wave is 1.5 to 50 MHz.

15. A transdermal drug administration device as described in any one of claims 11 to 14, wherein the molecular weight of the drug is 5 to 150 kDa.

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