JPH01500247A - Ultrasonic enhancement of transdermal drug delivery - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Ultrasonic enhancement of transdermal drug delivery Background of the invention FIELD OF THE INVENTION The present invention is generally in the field of drug delivery, and more particularly in the field of ultrasound-enhanced and and in the field of controlled transdermal drug delivery.

Drugs are usually administered either orally or by injection. most drugs Effectiveness depends on reaching a certain concentration in the bloodstream. any administration Some drugs have inherent side effects that cannot be eliminated depending on their form.

Many drugs exhibit undesirable behaviors that are particularly related to particular routes of administration. for example , the drug may be affected by the low pH in the stomach, localized enzymes, or food or drink in the stomach. It can be degraded in the gastrointestinal tract by interaction with substances. the drug or disease itself The body may prevent or impair absorption of the drug due to vomiting or diarrhea. There is. If the entire drug passes through the gastrointestinal tract intact, the liver The early-pass effect results in rapid metabolism to pharmacologically inactive forms. Become. Sometimes the drug itself has undesirable inherent properties (e.g.

(short half-life, high potency, or narrow range of therapeutic blood levels) Sometimes there is.

Recently, attempts to solve some of the problems with traditional dosage forms include Includes transdermal delivery of drugs. Topical administration is primarily for the treatment of localized skin diseases. It has been used for many years in medical treatment. However, local treatment In some cases, the drug penetrates the outer layer of the skin to treat the disease condition, but the drug does not reach the entire body. All that is required is that there is little or no accumulation of

The transdermal delivery system.

Specifically designed to obtain blood levels throughout the body. Transdermal penetration or transdermal Physical absorption is when a substance such as a drug passes from outside the skin through various layers of the skin and into the bloodstream. It can be defined as passing through.

Transport of drugs through the skin is complex as many factors affect their penetration. be. These factors include the structure and timing of the skin; the permeation molecules; physicochemical relationships between the skin and the supply matrix; and the skin, penetrants, and This includes the complete combination of supply and supply systems. Topical administration of drugs is particularly sensitive to skin penetration. The characteristics were taken into consideration. In many reports, chemical enhancers, i.e. keratin using molecules that penetrate the layer and reduce its resistance to drug permeation, or describes attempts to alter skin permeability by external means such as iontophoresis. It is being Dimethyl sulfoxide (DMSO) or 1-dodecyl aza Reagents such as cyclohebutan-2-one (Azone) are among the It tends to promote the permeation of drugs incorporated into it. however.

With the exception of iontophoresis, all of these systems require external control of the rate of drug release. There is no way to do that.

Fahim U.S. Pat. No. 4,309.989 teaches The use of sound waves to locally administer drugs has been disclosed. at least 1 Using ultrasound at a frequency of 1,000 KHz and an intensity of 1 to 3 W/ctfl, the simple Selective and local intracellular concentration of zinc-containing compounds for the treatment of herpes virus. It was done.

Important limitations of this disclosed method are the local administration of the drug and the The point is that it can only be used to localize within cells.

As shown in Figure 1, the skin has a complex structure. at least four different Tissue layers are present: epidermis without proliferative capacity (stratum corneum), epidermis with proliferative capacity, proliferative competent dermis (dermis), and subcutaneous connective tissue (hypodermis). stations within these layers. It contains the circulatory system of the skin, the arterial plexus, and the appendages (hair follicles, sebaceous glands). , and sweat glands). The circulatory system is located in the dermis and in the tissues below the dermis do. The exchange of nutrients between the epidermis and blood takes place by the mechanism of diffusion.

Capillaries do not actually belong to the epidermal structure and are located on the outer surface of the skin between 150 and 2 Exists within the range of 00μ.

As shown in Figure 1, skin permeation can occur by the following processes: (a) Transcellular penetration through the stratum corneum; (b) Intercellular penetration through the stratum corneum. and (C) penetration via the appendages (particularly the sebaceous pathway of the pilosebaceous organ and including the aqueous line pathway of the salt sweat glands). In the former two mechanisms, the remaining epidermis and dermis There is a need to further expand this area. In the third mechanism, the epidermis or leaked to.

Penetrates directly into the dermis.

Transdermal drug delivery has significant advantages over other systemic drug delivery methods. . However, despite these advantages, relatively few drugs can be delivered transdermally. That's it. Most drugs do not penetrate the skin quickly enough to have a therapeutic effect. stomach.

The steady-state skin permeability of drugs in vitro is 0 for digitoxin; 00013μg/c4・hr from low to 300μ for efuatorin It extends to g/afl/hr. To determine transdermal permeability, skin properties Several factors must be considered. For example, a skin through which a substance passes Skin types vary depending on the animal species. It also changes with age, and infants' skin It is highly permeable compared to adult skin.

It also depends on the local composition of the skin, thickness1 and density.

as a function of damage or exposure to organic solvents or surfactants, and even dry temperatures. It also changes as a function of certain diseases such as epidermal and epidermal excoriation. of clinically useful drugs For transdermal administration, some method of enhancing and controlling permeability must be found. I have to get it out.

Therefore, it is an object of the present invention to promote the permeation of molecules through the skin and into the circulatory system. The objective is to provide a method for controlling and controlling

Another object of the invention is the penetration of the skin from the outside into the skin or the drug introduced into the skin. The object of the present invention is to provide a method for promoting permeation of the agent without impairing any phase of the agent.

Still another object of the present invention is to obtain a therapeutically appropriate blood level of a drug. An objective of the present invention is to provide an improved method for the transdermal delivery of drugs when Ru.

Another object of the invention is to provide species containing molecules that are soluble in aqueous, inorganic or lipid solutions. To provide an improved method for transdermal delivery of drugs useful for various molecules. be.

Another object of the invention is that it is useful for both living and non-living skin, The goal is to provide many ways to

Still another object of the present invention is a method for promoting skin permeation of drugs, which method is simple and easy to use. Provides a method that is convenient, effective, reproducible, and economical There is a particular thing.

(Margin below) Summary of the invention The present invention is a method of promoting and controlling the transdermal permeation of molecules using ultrasound. child Molecules such as drugs, antigens, vitamins, inorganic compounds, organic compounds, and This includes various combinations of these substances. This molecule passes through the skin and into the circulatory system. reach. The frequency and intensity of the ultrasound energy delivered.

The medium between the ultrasound generator and the skin and the length of exposure time depend on the skin type. and determined according to the substance to be diffused transdermally. measured over time Under what conditions are the levels of diffuse molecules in blood and urine determined to be appropriate? It is first used to determine whether a transition occurs.

- In FIQ, the frequency range of ultrasound is between 20KH2 and 10MHz and the intensity is 9 is between OW/cffl and 3W/cffl. Frequency to prevent skin damage Decreasing the number reduces the strength. The preferred frequency range is 0.5MHz and 1.5MHz. 5MHz, and the preferred intensity range is between 2W/cffl and 4W/c%. It is between. For most medical applications, irradiation is performed for between 1 and 10 minutes. Ru. Ultrasound may be pulsed or continuous. However, one frequency The two intensities, and irradiation time depend on each other as well as on the diffusing molecules and irradiation. It is a function of the nature of the skin at the site.

One way to determine the maximum dose is to measure skin temperature. of the skin If the temperature increases by 1-2°C, the process is moderated or stopped.

In another embodiment of the invention, using ultrasound energy.

Facilitates the penetration of other molecules through non-living skin. for example.

Increases the rate at which preservatives or dyes diffuse into hides or fine fur.

Promotion of transdermal migration both in vivo and in vitro was demonstrated by radiolabeled 'H-D-mannitol and 3H-inulin penetrate the skin of rats and mice. This is illustrated by an example of what happens. 5-20 μl of 3H-D-manni Thor test solution was applied to the skin on the backs of hairless mice and on the upper backs of rats. First, an ultrasound gel was placed on the affected area.

Apply 20 μl of 3H-D-mannitol topically and then immediately apply 1.5-2 ．． We investigated the emission of radioactivity after irradiating OW/c+fl ultrasound for 2 to 3 minutes. The radioactivity excreted in the urine of sonicated rats in the first 2 hours was the same as that of controls. It was 20 times as large.

Brief description of the drawing FIG. 1 is a cross-sectional view of human skin.

Figure 2 depicts the diffusion of 'H-D-mannitol through the skin of rats and mice. This is a graph. −◇−◇− and ◆−◆− are for runts, respectively. These are the results with and without ultrasound irradiation. −〇−〇− and −・− ・− is the case of mice, with and without ultrasound irradiation, respectively. This is the result.

Figure 3 shows the results after topical application of 20 μCi of ('H)-D-mannitol. FIG. 2 is a graph showing the excretion of ('H)-D-mannitol into the urine of rats subjected to anaphylaxis.

−◇−◇− and one mumu are the results with and without ultrasound irradiation, respectively. This is the result.

No. 411ila-c is (a) (3H)-D-7nitol of 20.1/Ci .

(b) 10 μCi of (3H)-D-mannitol, and (C) 50 μCi of [ 3H] - in the urine of rats for 10 hours after topical application of inulin. 3 is a graph representing the percentage of 3H-drug excreted into −◇−◇− and one mu Mu is the result with and without ultrasound irradiation, respectively.

Figure 5 shows hairless mice treated for 10 hours after topical application of 5 μCi. It is a graph showing the percentage of (3H)-D-mannitol excreted into urine.

−◇−◇− and −Moum− are the results with and without ultrasound irradiation, respectively. This is the result.

Kotan■Former Takakume Escape The present invention improves the rate and penetration of drugs into and through the skin into the circulatory system. A method for increasing the effectiveness of

It involves exposing the skin to ultrasound waves at a predetermined rate. This ultrasonic wave passes through the stratum corneum. changes the migration of molecules. Such transitions occur between cells, within cells, and between cells. Occurs by penetration through the genital organs. Required ultrasonic irradiation time 9 frequencies and and strength depend on a variety of factors. Its factors include skin thickness and permeability. This includes skin resistance to These are 1 race, 1 year old, have any trauma or illness? It depends on whether or not the individual is placed, and the environment in which the individual is placed.

Ultrasound is a sound wave with a frequency above 20kHz. Used for therapeutic purposes in medicine The ultrasonic wave that can be used usually has a frequency of 1.6 to about 10M1 (z) It will be done. Here, in order to promote transdermal transfer of one molecule, 20 kHz and one molecule were used. between 0 and 3 W/c4, preferably 2 and 4 W/cffl at a frequency between Ultrasound with an intensity between . The preferred frequency range is between 0.5MHz and and 1.5 W/c'III. Equipment that emits pulsed ultrasonic waves and Any device that emits continuous ultrasonic waves may be used. The irradiation time is just A few seconds is sufficient. because.

This is because the response time to ultrasonic waves is extremely fast. Excessive irradiation may cause burns. Therefore, care must be taken. Skin temperature is one measure against over-irradiation It is a sign. In the present invention, human skin is maintained at a temperature below 38°C. be done.

In the examples below, in vivo sonication of rat and mouse skin was demonstrated. It will be done. The energy of the ultrasonic wave is 1 to 2 W/c+fl, and one frequency is 8 The frequency is 70kHz and the irradiation time is 1 to 3 minutes. rat and mouse skin lower frequencies (in the 75 kHz range) are recommended for in vitro treatment. This is done over a long period of time (up to 2 hours). The maximum effect of ultrasound is localized. This can be achieved by applying ultrasonic waves after application. After applying the drug locally, If ultrasound is applied after 10 hours, almost no effect will be observed. .

The particular implementation of the ultrasound generator is not critical. In the area where ultrasound is irradiated Depending, probes, baths and containers can all be used. A large number of devices are It's on sale. similar to high-voltage devices commonly used for mass vaccinations. Ultrasonic irradiation equipment makes percutaneous patient treatment faster, easier, and more repeatable. You will be able to return it.

Ultrasound waves do not propagate well in the air.Therefore, the ultrasound generator should not be placed between the skin and the skin. Preferably, a liquid medium is present. Either aqueous or inorganic gel type may also be used, including one of many commercially available products. be done. Preferably, the medium should have an absorption coefficient close to that of water. be. Alternatively, an ultrasound generator can be applied to a patch containing the molecules to be transferred transdermally. agents (e.g., drugs used to absorb drugs transdermally without the use of ultrasound) It is also possible to apply directly to a patch containing an agent. These patches generally include: Holds the protective cover, drug-containing matrix, support and the patch in place It consists of an adhesive that can be used.

The advantage of using ultrasound is that the speed and effectiveness of migration is improved It is. Under normal circumstances, drugs that do not penetrate the skin or enter the circulatory system can be irradiated with ultrasound. allows it to pass through the skin. By controlling frequency 9 intensity and irradiation time. The speed of migration is controlled. Measure concentration in blood or urine over time is used to determine what ultrasound irradiation conditions are appropriate. obtain.

In a preferred embodiment, ultrasound is applied to compounds such as large molecular weight or polar molecules. is used to facilitate the transfer of the drug through the patient's skin. of the applied drug Increase migration speed.

Greater control and drug utilization through directional control gender is achieved. Therefore, the proportion of drug that quickly enters the bloodstream increases and is unwanted. Side effects can be avoided.

Ultrasonic irradiation enables transdermal introduction of drugs. This irradiates ultrasound It would be impossible if you didn't. The ultimate goal is to get 9 molecules into the bloodstream, which is most desirable. The key is to introduce it quickly. The transdermal device used here, or Even low-molecular-weight drugs such as nitroglycerin are present in the bloodstream. It takes 30 minutes to enter. High-quality products such as catapresan Medications for hypertension take two days to fully enter the bloodstream. these drugs The time required for the drug to enter the bloodstream when administered orally ( It is highly desirable to reduce the time to a few minutes).

The safety and effectiveness of the methods disclosed herein are determined by the use of 3H-labeled mannitol and This is clarified by examples (including but not limited to) using inulin and inulin.

These compounds were selected for the following reasons. In other words.

D-mannitol is a highly polar sugar alcohol, and inulin has a molecular weight of It is a high (m, iy, 5200) polysaccharide and does not easily penetrate the skin. Therefore, Tooru It is possible to detect transient slight changes. And D-mannitol and inulin are all rapidly excreted. This reduces the amount of drug in the bloodstream. It is possible to monitor directly in vivo.

: In-vitro scene Changes in skin permeability caused by ultrasound energy were investigated in vitro using a two-chamber cell. Determined by Toro diffusion method. The diffusion cell consists of two separate compartments C4, 5ml and and 5.5d), with a 1.3cm diameter opening on the side of each compartment. They are designed to be tightened together through the sections. Magnetic stirring in each compartment Stir using a stirrer. Animals were killed with CO, and a piece of dorsal skin was excised. skin sample was held between the cells using a pressure clamp, with the stratum corneum facing the donor solution. . The donor compartment was filled with a buffered saline solution containing 0.1 M phosphate (pH 7, Add saturated D-mannitol solution from 3), and add 20 μCi of D-3) 1- into this. Contains mannitol. The receiver solution was buffered saline. fill with water This cell was placed in the center of an ultrasonic bath.

This ultrasonic bath is a RAI Research Corporation model 250 with automatic temperature control. 75kHz in a stainless steel water tank (3.5” x 3.5” x 2.5”) It generated ultrasonic waves with a frequency of . The permeability experiment was carried out for the first time after starting the ultrasound irradiation. It was carried out within 2 hours of. A 200 μl sample from the receiver solution was added over time. Collected 200μ! of buffered saline. Radioactivity of collected samples was measured by counting using a liquid scintillation counter. all fruit The experiments were conducted at room temperature (22°C). Controls were not exposed to ultrasound.

3H-D-mannitol diffusing in the skin of runts and mice in vitro. When a cell containing a solution was irradiated with 75kHz ultrasonic waves for 2 hours, the result was as shown in Figure 2. Penetration of sea urchin drugs increased by 50-80%. skin before injecting the drug into the donor cell. A similar effect was observed when the skin was irradiated for 2 hours.

Ultrasound irradiation did not reduce skin permeability in mice.

However, in SEM research, ultrasonic waves of 1.5 W/cffl at 870 kHz When compared to control skin or mouse skin exposed to waves in vivo for 1 minute, 7 The skin of mice was irradiated with high-intensity ultrasound at 5 kHz for 2 hours in vitro. A considerable degree of mechanical tearing is seen on one surface.

1 Arashi 1 Otsu Iiromachi Bodo - Nuclear history i Skin 1 Permeability 9 - Danbari in vivo, and Effects on skin permeation of D-3H-mannitol and 3H-inulin in mice The effects of ultrasonic energy were tested.

Subuchi Gudawley (CD)! Rats (weighing 200-250 g each) and Hairy mice were used in this example. Conditions are in place to minimize extrinsic skin damage. set. This in vivo ultrasound treatment device (Prudic UT42UA) It was used in the experiment. This device treats by a combination of 5 mechanical and thermal effects. approved for use in processing human and animal tissue to facilitate It is.

A test solution of 5-20μr D-”!(-mannitol was applied to the hair on the upper back of the rat. It was applied to the shaved area, and then a water-soluble ultrasound gel was applied there. in vivo Changes in the skin surface were observed using electron microscopy techniques for both the and in vitro experiments. Examined.

To perform scanning electron microscopy (SEM) examination, the dorsal surface of the mouse and rat was The skin pieces were fixed with 2% glutaraldehyde.

Then treated with 1% osmium tetroxide and in alcohol (continuously) (increasing concentration). Next.

It was dried to critical point and examined under the electron microscope.

Measuring the amount of drug excreted in the urine is essential for determining permeation rates in in vivo experiments. It was plain. The rat was placed directly opposite the restrainer with urine inserted into the bladder. 10 μr Test solution of 38-D-mannitol and 12.5-50 ul of 3H-inulin was applied to the skin and then irradiated with ultrasound. 15-30 for the first 2 hours of urine Collected minute by minute, and then several locations later. Volume and release of each urine sample The radioactivity was measured.

Urine samples from sonicated and control rats were placed on silica plates. Comparison was made by thin layer chromatography. This silica plate is made of t-butanol. :pyridine:water (6:4:3) and phosphomolybdic acid Visualized by reagent. Spread this silica gel plate so that the spots are relative to each other. Cut into several sections according to the distance M (l) that was moved, and cinch each in a ration vial. Add 1 mfl of distilled water to each vial and add the drug. melted.

Aquasol, New England, New Claire, Boston.

MA) scintillation solution 10- was added and radioactivity was measured.

Figure 3 shows radioactively labeled 'H-D-mannitol 20μ! apply locally 25 then immediately 1.5-2.0 W/cn for 2-3 minutes! Perform ultrasonic treatment with The excretion of 'lL, D-manni, and toll after This is compared to the emissions caused by (not). Sonicated rats were the first During the 2-hour period, they had 20 times more radioactivity in their urine than the control rando.

The effectiveness of ultrasound decreased over time. After 10 hours, those two groups Radioactivity in the urine was indistinguishable. The difference in the release rate of HD-mannitol is extremely It was observed only when sonication was performed immediately after drug administration. these rats when treated with ultrasound, its release for 10 hours or more after drug administration. No change was observed in the exit speed.

Mannitol is completely and quickly removed from the body and is therefore completely present in the urine. appear. As assessed by thin-layer chromatography, molecules transmitted by ultrasound The effect is that mannitol is not broken down by ultrasonic energy. showed that.

Figure 4 shows rats receiving both 3+(-D-mannitol and 3H-inulin) topically. Specific time interval for the total amount of radioactivity released over 10 hours after washing This figure compares the percentage of [3H] discharged in the following cases. This is a relative medicine This was used as a measure of drug penetration. In sonicated rats, the first 2 hours The percentage of [3H] excreted during the period is 20% for 3H, D-mannitol. 30%, and 50% for 3H-inulin. In contrast, each control For 3N (2-5% for -D-mannitol and 3H- Regarding phosphorus, it was 10%. As shown in Table 1, the relative rate of drug permeation R is defined by the following formula: Here, Pus is divided by the total amount of ('H) excreted in the urine over 10 hours. can be obtained. The percentage of [3H] in the urine of sonicated rats at a certain time t be. Pct is excreted by rats over 10 hours [divided by the total amount of 3H1]. That's what you get.

Percentage of [3H] in the urine of untreated rats at a certain time t. From table 1 Thus, skin permeation of both drugs was significantly reduced during the first 2 hours in sonicated rats. The results were 6 to 20 times greater than those of the matched control group.

(Margin below) No LL ``剋 Zunweek Qzu vs. North in rats Time D-3H-mannitol 3H-inulin (hour) 20mC110mC 150mC152,51,51,5 Figure 5 shows 5μ! 1-1.5 W/cf immediately after application of D-'H-mannitol. Relative of D-mannitol in mice after 1 minute of sonication of fl. It shows transparency. The results show that the amount of [3H] released at a specific time is 10 It is expressed as a percentage divided by the total amount of [3H] excreted over time.

Even when ultrasonic treatment was performed 10 hours after application of the drug, the amount of radioactivity released was 100%. There was no change in the fraction.

These examples include “H-D-mannitol and 3H-inulin in case 7) We show that transdermal permeability increases 6-20 times during the first 2 hours after sonication. are doing. This increase occurs during the early stages of transdermal penetration, before a steady state is reached. was observed only. D-mannitol in rats by ultrasonic energy Although the lag time of transdermal penetration of inulin and inulin was reduced, the drug The fact that there was no change in the release rate suggests that: One Therefore, what is enhanced by ultrasonic treatment is the ability to penetrate the stratum corneum of rat skin itself. Diffusion of the administered drug through alternative channels such as hair follicles etc. It is suggested that this is because of the

When the intensity of ultrasound having a frequency of 1 old C is 5 W/c + fl, there is a significant No increase in temperature and no harmful effects on the skin of mice or rats capable of growth did not occur. Rats were exposed to 3W/cffl unconventional ultrasonic energy for 3 minutes. 1.5W/cffl ultrasonic sound to the mouse if applied for the rotation time or When wave energy is applied for 1 minute, skin temperature does not increase by more than 1°C. won. Longer treatment times caused skin burns at 9 o'clock.

In short, both in vivo and in vitro.

These examples using skin from two species illustrate the first order. In other words Ultrasound is an effective way to accelerate the movement of molecules through the skin and into the circulatory system. It is explained that it is a means. The frequency, power and application time depend on your skin type. Optimized to suit each individual case, taking into account both the molecules and the molecules to be diffused. It can be done.

Although the invention has been described with respect to specific embodiments, it is possible to A modification of this method that uses ultrasound energy to promote the migration of all molecules It is believed that modifications and variations may occur to those skilled in the art. Such modifications and All modifications and variations are within the scope of the appended claims.

FIGURE 2 0 4 8 + 2 16 20 24 FIGtJRE　3 Ya, 1-(- Chain Senkiri 4 marks $fI, 1 in) FIGURE 4A FIGURE 5 international search report

Claims (14)

[Claims] 1. A method of promoting and controlling transdermal delivery of molecules, comprising: a) the molecule to be delivered; to select; b) containing the molecule in a medium with an absorption coefficient similar to that of water; and c) applying ultrasound to the molecules in the medium at a frequency between 20kHz and 10MHz; Controlled intensity between 0W/cm2 and 3W/cm2 without damaging the skin irradiating for a selected period of time to induce transdermal introduction of the molecule at a rapid rate. A method that includes and; 2. The method according to claim 1, wherein the frequency of the ultrasonic wave is 0. Power between 5MHz and 1.5MHz and between 2W/cm2 and 4W/cm2 irradiated at 300°C. 3. The method according to claim 1, wherein the ultrasound is applied for less than 10 minutes. shot. 4. The method according to claim 1, wherein the medium is an aqueous gel. 5. The method according to claim 1, wherein the medium includes a support, an adhesive, and a drug. It is a transdermal drug-absorbing patch that includes a drug-containing matrix and a protective cover. . 6. The method according to claim 1, wherein the ultrasonic waves are continuously irradiated. . 7. The method according to claim 1, wherein the ultrasonic waves are irradiated in a pulsed manner. Ru. 8. 2. The method according to claim 1, wherein the molecule is a protein, a drug, or an anti-inflammatory agent. molecules, vitamins, inorganic compounds, organic compounds, and combinations thereof the molecule has a biological effect when introduced into the circulatory system. . 9. The method according to claim 1, wherein the method comprises: The method further includes measuring the temperature of the skin. 10. The method according to claim 1, wherein the ultrasonic waves have a certain frequency and irradiated at such an intensity that the skin temperature does not rise above 2°C. It will be done. 11. A method according to claim 1, wherein the method comprises: further comprising measuring the concentration of the offspring. 12. 12. The method according to claim 11, wherein the method comprises increasing the concentration of the molecule. measuring the transdermal transcutaneous translocation rate of the molecule at a specific frequency. , intensity, and duration of ultrasound irradiation. 13. 13. The method according to claim 12, wherein the method comprises: , and the transdermal migration speed of the molecules by changing the ultrasound irradiation time. It further includes optimizing. 14. 2. The method of claim 1, wherein the molecule comprises a dye, a preservative, and a preservative. and other molecules for treating leather and fur.