Transdermal drug delivery methods and devices

Abstract

The present invention provides a method and device for promoting transdermal release of drugs by using an ultra-high frequency resonator to generate bulk acoustic waves. The method of the present invention can achieve transdermal release of substances that are difficult or impossible to penetrate the skin, including but not limited to small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other biologically active substances.

Description

[0001] This application claims priority to the following Chinese patent application: Application number 201910496314.8, filed on June 10, 2019, entitled “Transdermal drug delivery method and device”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to a drug release method and device. More specifically, the present invention relates to a method and device for promoting transdermal drug release by using an ultra-high frequency resonator to generate bulk acoustic waves. The method of the present invention can achieve transdermal release of substances that are difficult or impossible to penetrate the skin, including but not limited to small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other biologically active substances. Background Art

[0003] The skin covers the surface of the human body and is in direct contact with the external environment. It prevents foreign substances from entering the human body and has an important protective function. The skin is composed of the epidermis and dermis, which are closely combined. The epidermis is composed of stratum corneum, which is divided into stratum lucidum, stratum granulosum and stratum germinativum from shallow to deep. The stratum corneum is composed of multiple layers of keratinized epithelial cells (nuclei and organelles disappear, and the cell membrane is thicker) and intercellular lipids. It is lifeless and impermeable. It has the functions of preventing the outflow of tissue fluid, anti-friction and anti-infection. It is the main barrier for the absorption of exogenous substances through the skin. The dermis is composed of dense connective tissue, which is divided into papillary layer and reticular layer from shallow to deep. The reticular layer is connected to the subcutaneous tissue. It is rich in collagen fibers, elastic fibers and reticular fibers, which are interwoven into a network, making the skin more elastic and tough.

[0004] The general term "transdermal" as used herein refers to the release of an active agent (e.g., a therapeutic agent such as a drug, or an immunologically active agent such as a vaccine) through the skin to local tissues or the systemic circulatory system, substantially without cutting or piercing the skin, such as cutting with a scalpel or piercing the skin with a hypodermic needle. The advantages of transdermal drug delivery systems are: drug absorption is not affected by factors such as pH, food, and transit time in the digestive tract; avoids the first-pass effect in the liver; overcomes adverse reactions caused by excessive blood drug concentrations due to rapid absorption; can continuously control the speed of administration, and is flexible in administration, etc.

[0005] In the skin drug delivery system, the epidermis, especially the stratum corneum, is the main barrier for drugs to enter the body. Studies have found that only a very small number of drugs have excellent skin permeability, and most drugs are not easy to pass through the effective and selective barrier of human skin. The epidermis, especially the stratum corneum, is the main barrier layer. Once its protective function is lost, a large number of water-soluble, non-electrolyte molecules will diffuse into the body circulation at a speed of thousands of times. Therefore, promoting the transdermal absorption of drugs is mainly to reduce the obstacles of this barrier layer.

[0006] At present, the main technologies for dynamically opening the dense structure of the stratum corneum to promote transdermal drug delivery include chemical permeation, physical permeation (conductivity, microneedles), etc. Chemical permeation is mainly achieved by a substance that can reversibly change the barrier function of the stratum corneum without damaging any active cells, enhance the ability of drugs to penetrate the skin, and increase the amount of drugs that penetrate the skin. The advantage of chemical permeation is that it can be integrated with drug preparations, but when used in large quantities or for a long time, it will cause skin redness, swelling, pain and other irritations. Compatibility with drug ingredients is also an important factor restricting its application.

[0007] Commonly used single physical technology penetration promotion methods include microneedles, electrets, ions, electroporation, lasers, magnetic field introduction, and thermal perforation. Microneedle penetration promotion is to apply a transdermal patch composed of dozens to hundreds of hollow or solid microneedles to the skin, penetrate the stratum corneum barrier and create tiny channels in the epidermis. The drug enters the systemic circulation through the tiny channels, which can promote the percutaneous penetration of the drug to specific parts. It is suitable for large molecule drugs (such as peptides, proteins and vaccines with low skin permeability). Electroporation technology refers to a method in which the directional arrangement of lipid molecules in the stratum corneum of the skin changes under the action of an instantaneous high-voltage pulse current, increasing the disordered structure of the lipid bilayer to form short-term, reversible hydrophilic channels, thereby improving the permeability of cell and tissue membranes. It is suitable for small molecule drugs with good ionization performance (such as insulin), but its reliance on charged devices and energy has limited its promotion. Laser technology is a physical penetration enhancement technology that uses the photomechanical waves formed by laser impacting the target substance to impact the skin. The energy generated ablate or erode the stratum corneum, change the molecular arrangement of the body's tissues, form dense channels, and thus promote the transdermal absorption of large molecular drugs. Magnetic field introduction penetration enhancement is a physical technology that uses a magnetic field to increase the transdermal permeability of drugs. Thermal perforation technology is a technology that uses pulse heating to form hydrophilic channels in the stratum corneum to increase skin permeability. Although magnetic field introduction and thermal perforation technology can currently improve the transdermal permeability of drugs, the complexity and high cost of production are difficult problems that need to be overcome urgently.

[0008] Methods of using ultrasound to introduce drugs have been reported, but their specific mechanism of action has not yet been fully elucidated. The current mainstream view is that cavitation is the most important mechanism of ultrasound penetration. Cavitation refers to the process of gas bubble formation, expansion, contraction and collapse during the propagation of ultrasound in a medium. Existing research results show that the lower the frequency, the better the cavitation effect [Hideo U, et al., Pharmacy Bullet, 2009, 32 (32); 916-920]. Therefore, the use of low-frequency (especially 20KHz) ultrasound and the use of some surfactants to reduce the surface tension of the liquid medium are the main research directions for improving the cavitation effect and increasing drug permeability.

[0009] Ultrasonic waves refer to ultra-high frequency longitudinal sound waves with a frequency exceeding 0.3 GHz, which are mainly used in the field of communication. Since the prior art is well-known for the penetration-promoting effect of low-frequency ultrasound, ultra-high frequency sound waves have never been applied to biological penetration-promoting applications. In 2017, Duan Xuexin et al. found that ultra-high frequency ultrasonic waves (1.6 GHz, 300 mW) can instantly form nanopores in the cell membrane, allowing drug molecules, DNA fragments, and gene lipid particles to pass through the cell membrane and enter the cytoplasm [Duan Xuexin et al., small 2017, 1602962]. Further research results show that it can be used for drug loading and release in bilayer lipid membranes and liposomes [Duan Xuexin et al., Angew.Chem.Int.Ed.10.1002 / anie.201810181]. However, the public literature is limited to the effects on cell membranes or cell membrane-like bilayer liposomes. The stratum corneum that limits the transdermal effect is composed of multiple layers of keratinized epithelial cells (the nucleus and organelles have disappeared, and the cell membrane is thicker) and tightly packed intercellular lipids. It is lifeless and impermeable. The composition, density and thickness of the components are very different from the structure of the cell membrane. Therefore, it is impossible to judge the feasibility and safety of the application of this technology in physical promotion of transdermal penetration.

[0010] There is also a need in the art for effective and safe transdermal drug delivery methods and devices. Summary of the invention

[0011] The present invention provides a novel method and device for transdermal delivery of bioactive substances by using an ultra-high frequency resonator to generate bulk acoustic waves, especially for transdermal delivery of drug molecules that are difficult or impossible to transdermally deliver. The method provided by the present invention can effectively and safely deliver small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other biological drugs.

[0012] Specifically, the present invention provides a method for administering a bioactive agent to a patient via transdermal delivery, the method comprising:

[0013] (1) providing a reservoir containing a biologically active agent, wherein the reservoir is used to contain a solution, suspension or gel containing the active agent,

[0014] (2) activating one or more ultra-high frequency acoustic wave resonators to generate bulk acoustic waves with a frequency of about 0.5-50 GHz in the solution, suspension or gel, so that the bioactive agent enters or penetrates the patient's skin.

[0015] As used herein, the term "transdermal" refers to the delivery of a drug into and / or through the skin for local or systemic therapeutic purposes.

[0016] Patient refers to humans or other animals, including but not limited to other primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, sheep, pigs, goats and horses; domestic animals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other Galliformes, ducks, geese, etc.

[0017] A bioactive agent refers to a composition of matter or mixture containing an active agent or drug that is pharmacologically effective when administered to a patient in a therapeutically effective amount. Examples of bioactive agents include, but are not limited to, small molecular weight compounds, polypeptides, proteins, oligonucleotides, nucleic acids, and polysaccharides.

[0018] In the method of the present invention, the molecular weight of the bioactive agent ranges from 200 to 1,000,000 Daltons.

[0019] In the method for the present invention, the bioactivator can also be delivered by being attached to a carrier. The carrier can be any solid matrix used for fixing in biotechnology. Such a carrier can be a particle, sheet, film, gel, filter, microtiter band, tube or plate. Specific carriers of interest include silica, glass, inorganic carriers such as metal nanoparticles or aluminum oxide, organic carriers such as polymer carriers (such as polystyrene). Preferably, the solid carrier is a polymer particle, particularly polymer microparticles, and a diameter of 50nm to 500 μm, for example 100nm to 100 μm.

[0020] Examples of "biologically active agents" include, but are not limited to, luteinizing hormone-releasing hormone (LHRH); LHRH analogs (e.g., goserelin, leuprolide, buserelin, triptorelin, gonadorelin and napfarelin, urogonadotropins (follicle stimulating hormone (FSH) and LH)); vasopressin; desmopressin; adrenocorticotropic hormone (ACTH); ACTH analogs such as ACTH (1-24); calcitonin; vasopressin; desamino [Val4, D-Arg8] arginine vasopressin; alpha interferon; beta interferon; gamma interferon; erythropoietin (EPO); granulocyte macrophage colony stimulating factor (GM-CSF); granulocyte colony stimulating factor (G-CSF); interleukin-10 (IL-10); glucagon; growth hormone releasing factor (GHRF); insulin; insulinotropic; calcitonin; octreotide; endorphin; TRN; NT-36 (chemical name: N-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide); liprecin; αANF; βMSH; somatostatin; bradykinin; growth hormone; platelet-derived growth factor-releasing factor; chymopapain; cholecystokinin; chorionic gonadotropin; epoprostenol (platelet aggregation inhibitor); glucagon; bivalirudin; interferon; interleukin; urokinase (follicle-stimulating hormone (FSH) and LH); oxytocin; streptokinase; tissue plasminogen activator; urokinase; ANP; ANP clearance inhibitors; BNP; VEGF; angiotensin II antagonists; vasopressin agonists; bradykinin antagonists; ceredase; CSI's; calcitonin gene-related peptide (CGRP); enkephalins; FAB fragments; IgE peptide inhibitors; IGF-1; neurotrophic factors; colony stimulating factors; parathyroid hormone and agonists; parathyroid hormone antagonists; prostaglandin antagonists; pentegitide; protein C; protein S; renin inhibitors; thymosin alpha-1; thrombolytics; TNF; vasopressin antagonist analogs; alpha-1 antitrypsin (recombinant); TGF-β; fondaparinux; ardeparin; dalteparin; defibrotide; enoxaparin; hirudin; nadroparin; reviparin; tinzaparin; pentosan polysulfate; oligonucleotides and oligonucleotide derivatives such as formivirsen; alendronic acid; clodronic acid; etidronic acid; ibandronic acid; incadronic acid; pamidronic acid; risedronic acid; tiludronic acid; zoledronic acid; argatroban; RWJ445167; RWJ-671818; fentanyl; remifentanil; sufentanil; alfentanil; lofentanil; carfentanil and mixtures thereof.

[0021] The method of the present invention is particularly suitable for pharmaceutical active agents that are not easy or cannot be transdermal. For example, bulky active agents such as polypeptides or proteins. Among them, proteins can include cytokines, hormones, vitamins, surface receptors, haptens, antigens, antibodies, enzymes, growth factors, recombinant proteins, toxins, and fragments and combinations thereof. In addition, there are various small molecule drugs in the art that are not suitable for or cannot be passed through conventional transdermal preparations due to physical properties such as hydrophobicity.

[0022] In one aspect of the invention, the active agent is present in a solution or suspension. In another aspect of the invention, the solution or suspension is in contact with the patient's skin. In another aspect of the invention, the solution or suspension is in contact with the patient's skin through a semipermeable membrane. The solution or suspension can be added directly to the reservoir of the device of the present invention, and the upper surface of the reservoir is encapsulated with the semipermeable membrane. The solution or suspension can also be provided in a pre-packaged form. The encapsulated material includes a semipermeable membrane.

[0023] In the method of the present invention, the solution or suspension contains a solvent in which the various bioactive agents are soluble. In one aspect of the present invention, the solvent contained in the solution or suspension is an aqueous solvent, such as water. In another aspect of the present invention, the solution may also include a non-aqueous solvent such as ethanol, chloroform, ether, propylene glycol, polyethylene glycol, etc. In the method of the present invention, in addition to the bioactive agent, the solution or suspension may also contain an inert filler; a penetration enhancer; an excipient and other drugs or conventional components of transdermal devices known in the art.

[0024] In the method of the present invention, the semipermeable membrane is a semipermeable membrane through which the active agent cannot diffuse freely. The semipermeable membrane that can be used in the method of the present invention refers to various natural and artificial membranes known in the industry that have selective retention of compounds of different molecular weights, including but not limited to collodion semipermeable membranes, parchment semipermeable membranes, polymer semipermeable membranes such as cellulose ester membranes, regenerated cellulose membranes, polypropylene membranes, etc.

[0025] In the method of the present invention, the bioactive agent may be present in the solution or suspension in any possible content. The appropriate content may be determined by reference to transdermal preparations known in the art, or by testing using known methods. For example, since the method of the present invention can adjust the amount of the transdermal active agent by controlling various parameters of the sound waves generated by the ultra-high frequency sound wave resonator, the appropriate content in the solution or suspension may be detected and selected by experiments to ensure that the active agent is administered to the patient in a therapeutically effective and safe amount.

[0026] In the method of the present invention, a reservoir containing a bioactive agent is used. The reservoir is suitable for containing a solution, a suspension or a gel. The solution or suspension of the active agent can be directly added to the reservoir, and then the upper surface of the reservoir is encapsulated with a semipermeable membrane, or it can be provided in a pre-packaged form. The encapsulated material can be a semipermeable membrane, etc. For example, the reservoir has four frames for containing a solution or a suspension or a gel. For another example, the reservoir has two to four frames or slots for containing a packaging bag for a solution or a suspension.

[0027] In the method of the present invention, an ultra-high frequency (about 0.5-50 GHz) body acoustic wave is generated in a solution using an ultra-high frequency acoustic wave resonator. Particles (such as bioactive agents) in the body acoustic wave region formed by the ultra-high frequency are subjected to the combined effects of the fluid drag force (Stokes drag force), the inertial lift force (inertial lift force) generated by the laminar flow, and the acoustic radiation force (acoustic radiation force) caused by the attenuation of the acoustic wave. Under appropriate conditions (the properties of the solution and the particles, the intensity of the body acoustic wave, the distance the particles move, etc.), the body acoustic wave triggers the particles in the solution to flow along the direction of the acoustic wave propagation, and can pass through the skin and enter the inside of the skin without causing irreversible damage to the skin.

[0028] The ultra-high frequency acoustic wave resonator used in the present invention can generate ultra-high frequency (about 0.5-50GHz) vibrations, and induce body acoustic waves of corresponding frequencies in the solution. In one aspect of the present invention, the ultra-high frequency acoustic wave resonator is a thin film bulk acoustic wave resonator (FBAR) or a solid-state assembly type resonator (SMR), preferably a solid-state assembly type resonator. In another aspect of the present invention, the ultra-high frequency acoustic wave resonator is an acoustic wave resonator in a thickness stretching vibration mode, and a piezoelectric material thin film layer is grown in a vertical direction and excited to vibrate by coupling a vertical electric field through a d33 piezoelectric coefficient. The ultra-high frequency acoustic wave resonator used in the present invention can generate a localized acoustic flow at the interface between the device and the liquid without the help of a coupling medium or structure. The acoustic wave resonator of the present invention includes an acoustic wave reflection layer, a bottom electrode layer, a piezoelectric layer and a top electrode layer arranged in sequence from bottom to top. The overlapping area of ​​the bottom electrode layer, the piezoelectric layer, the top electrode layer and the acoustic wave reflection layer constitutes a body acoustic wave generation area. The top surface of the ultra-high frequency acoustic wave resonator is arranged on the wall of a container containing liquid (e.g., the bottom of the reservoir of the present invention), and generates a bulk acoustic wave with a propagation direction perpendicular to the wall toward the opposite wall; the area formed by the top surface can be called the bulk acoustic wave action area. The thickness of the piezoelectric layer of the ultra-high frequency acoustic wave resonator of the present invention ranges from about 1nm to 2um. The frequency of the ultra-high frequency acoustic wave resonator of the present invention is about 0.5-50GHz, preferably about 1-10GHz.

[0029] In the present invention, the shape of the acoustic wave action area can be any shape. In one aspect of the present invention, the width of the body acoustic wave generation area of ​​the ultra-high frequency acoustic wave resonator is about 50-300 μm, for example, about 70-150 μm. In another aspect of the present invention, the area of ​​the body acoustic wave generation area of ​​the ultra-high frequency acoustic wave resonator is about 1000-50000 μm. 2 , preferably about 5000-20000 μm 2 .

[0030] In one aspect of the present invention, in the method of administering a bioactive agent to a patient via transdermal delivery, the distance between the ultra-high frequency acoustic wave resonator and the patient's skin is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1-10 mm.

[0031] The inventor of the present application unexpectedly found that when the distance between the ultra-high frequency acoustic wave resonator and the patient's skin is about 0.1-20mm, the active agent can be effectively permeated through the skin, while the activity of biomolecules such as proteins can be maintained, and the transdermal efficiency is high. In another aspect of the present invention, the height of the reservoir is about 0.1-20mm, preferably 0.5-15mm, and most preferably about 1-10mm. During administration, the upper surface of the reservoir contacts the patient's skin, so the height of the reservoir is equivalent to the distance between the ultra-high frequency acoustic wave resonator and the patient's skin.

[0032] In one aspect of the present invention, the efficiency of transdermal delivery of bioactive agents can be adjusted by the power of the bulk acoustic wave. The microfluidic device adjusts the power of the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator by a power adjustment device. The output power of the power adjustment device is about 0.1-50W, preferably 0.2-10W, and more preferably 0.5-5W.

[0033] The bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator is driven by a signal from a high frequency signal generator. The pulse voltage signal driving the resonator can be driven with pulse width modulation, which can generate any desired waveform, such as a sine wave, square wave, sawtooth wave or triangle wave. The pulse voltage signal can also have an amplitude modulation or frequency modulation start / stop capability to start or eliminate the bulk acoustic wave.

[0034] In one aspect of the present invention, a device for administering an active agent to a patient via transdermal delivery is also provided. The device comprises:

[0035] A reservoir for containing an active agent; the reservoir is used to contain a solution or suspension containing an active agent;

[0036] One or more ultra-high frequency bulk acoustic wave resonators are arranged at the bottom of the reservoir, and the one or more ultra-high frequency bulk acoustic wave resonators generate bulk acoustic waves with a frequency of about 0.5-50 GHz in the solution or suspension. The solution or suspension containing the active agent contacts the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are arranged at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonators are arranged so that the propagation direction of the bulk acoustic waves generated in the solution or suspension is toward the top of the reservoir, that is, the surface in contact with the patient's skin.

[0037] In one aspect of the present invention, the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot diffuse freely. In one aspect of the present invention, the outer surface of the semipermeable membrane may also have a peelable closure film, which is peeled off before use (contact with the patient's skin).

[0038] In one aspect of the present invention, the reservoir has an opening or aperture suitable for adding a solution or suspension, or for loading a packaging bag containing a solution or suspension.

[0039] In one aspect of the present invention, the device further comprises a housing, and the reservoir is detachably connected to the housing. The housing has a mechanism suitable for fixing to a human or animal body so that the upper surface of the reservoir remains in contact with the skin, such as a buckle.

[0040] In one aspect of the present invention, the UHF resonator in the device has a circuit for receiving a pulse voltage signal. For example, the UHF resonator has a circuit and an interface for receiving a connection with an external high-frequency signal generator, and the interface is provided on the device housing. For another example, the UHF resonator has a circuit for receiving a radio frequency signal. When the active agent needs to be administered for a long time or at a fixed time, the device also includes a timing transmission signal system to excite the UHF BAW resonator at a specified time or time period.

[0041] In one aspect of the present invention, the bioactive agent is a small molecule compound, a polypeptide, a protein, an oligonucleotide, a nucleic acid and a polysaccharide.

[0042] In one aspect of the present invention, the molecular weight of the bioactive agent is 200 to 1,000,000 Daltons.

[0043] In one aspect of the present invention, the ultra-high frequency acoustic wave resonator in the device is a thin film bulk acoustic wave resonator or a solid-state assembly type resonator, for example, an acoustic wave resonator in a thickness stretching vibration mode.

[0044] In one aspect of the present invention, the height of the reservoir (bottom to top, such as the distance to the semipermeable membrane at the top) is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1-10 mm. During administration, the upper surface of the reservoir contacts the patient's skin, so the height of the reservoir is equivalent to the distance between the ultra-high frequency acoustic wave resonator arranged at the bottom of the reservoir and the patient's skin.

[0045] In one aspect of the present invention, the area of ​​the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator in the device is about 1000-50000 μm 2 , preferably about 5000-20000 μm 2 .

[0046] In one aspect of the present invention, the power of the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator in the device is about 0.1-50W, preferably 0.2-10W, and more preferably 0.5-5W.

[0047] In one aspect of the present invention, a transdermal composition is provided, comprising:

[0048] a reservoir containing a solution or suspension containing the active agent;

[0049] One or more ultra-high frequency bulk acoustic wave resonators are detachably arranged at the bottom of the reservoir, and the one or more ultra-high frequency bulk acoustic wave resonators generate bulk acoustic waves with a frequency of about 0.5-50 GHz in the solution or suspension. The solution or suspension containing the active agent contacts the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are arranged at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonators are arranged so that the propagation direction of the bulk acoustic waves generated in the solution or suspension is toward the top of the reservoir, that is, the surface in contact with the patient's skin.

[0050] In one aspect of the present invention, the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot diffuse freely. In one aspect of the present invention, the outer surface of the semipermeable membrane may also have a peelable closure film, which is peeled off before use (contact with the patient's skin).

[0051] In one aspect of the present invention, the reservoir has an opening or aperture suitable for adding a solution or suspension, or for loading a packaging bag containing a solution or suspension.

[0052] In one aspect of the present invention, the UHF resonator in the composition has a circuit for receiving a pulse voltage signal. For example, the UHF resonator has a circuit and an interface for receiving a connection with an external high-frequency signal generator, and the interface is arranged on the device housing. For another example, the UHF resonator has a circuit for receiving a radio frequency signal. When the active agent needs to be administered for a long time or at a fixed time, the device also includes a timing transmission signal system to excite the UHF BAW resonator at a specified time or time period.

[0053] In one aspect of the present invention, the bioactive agent is a small molecule compound, a polypeptide, a protein, an oligonucleotide, a nucleic acid and a polysaccharide.

[0054] In one aspect of the present invention, the molecular weight of the bioactive agent is 200 to 1,000,000 Daltons.

[0055] In one aspect of the present invention, the ultra-high frequency acoustic wave resonator in the composition is a thin film bulk acoustic wave resonator or a solid-state assembly type resonator, for example, an acoustic wave resonator in a thickness stretching vibration mode.

[0056] In one aspect of the present invention, the height of the reservoir in the composition (from bottom to top, such as the distance to the semipermeable membrane at the top) is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1-10 mm. During administration, the upper surface of the reservoir contacts the patient's skin, so the height of the reservoir is equivalent to the distance between the ultra-high frequency acoustic wave resonator arranged at the bottom of the reservoir and the patient's skin.

[0057] In one aspect of the present invention, the area of ​​the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator in the composition is about 1000-50000 μm 2 , preferably about 5000-20000 μm 2 .

[0058] In one aspect of the present invention, the power of the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator in the composition is about 0.1-50W, preferably 0.2-10W, more preferably 0.5-5W. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0060] Figure 1A diagram showing an exemplary experimental equipment setup of the present invention.

[0061] Figure 2 An exemplary ultra-high frequency acoustic wave resonator of the present invention is shown.

[0062] Figure 3 A schematic diagram showing an exemplary embodiment of the transdermal administration composition of the present invention. DETAILED DESCRIPTION

[0063] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0064] Example 1 Experimental apparatus and material preparation

[0065] according to Figure 1 The experimental device is set up as shown. It includes two upper and lower wells with adjustable heights surrounded by polydimethylsiloxane (PDMS) material walls. The lower well is closed and connected to a circuit board with an ultra-high frequency acoustic wave resonator to form a liquid supply pool that can accommodate liquid or gel. In the experiment, the volume of the liquid supply pool was adjusted to about 30μL and the height was about 1mm. The top of the liquid supply pool was covered with a semipermeable membrane and / or mouse skin. A solution or gel containing active substances was added to the liquid supply pool. The resonator can generate bulk acoustic waves with a frequency of about 0.5-50GHz in the liquid in the chamber that are transmitted to the top. The upper well and the liquid supply pool are separated by a semipermeable membrane and / or an animal skin sample according to different experiments. Solutions such as PBS can be added to the upper well to receive active substances that pass through the liquid supply pool, also known as a receiving pool.

[0066] Figure 2 This is a photo of an exemplary ultra-high frequency acoustic wave resonator, i.e., a physical object of a special acoustic wave, in the method and device of the present invention. The area of ​​the generated bulk acoustic wave is about 15000-20000 μm 2 . Figure 2 The image on the left shows the ratio of the UHF acoustic wave resonator device to a coin. Figure 2 The figure on the right shows the area and pattern of bulk acoustic waves generated by the ultra-high frequency acoustic wave resonator (the pattern shown in the figure is a pentagon).

[0067] Figure 3 It is a schematic diagram of a transdermal drug delivery composition provided by the present invention.

[0068] The transdermal composition comprises a reservoir 10 for containing an active agent; the reservoir is used to contain a solution or suspension 20 containing the active agent; and a plurality of ultra-high frequency bulk acoustic wave resonators 30 are arranged at the bottom of the reservoir, wherein the one or more ultra-high frequency bulk acoustic wave resonators generate bulk acoustic waves with a frequency of about 0.5-50 GHz in the solution or suspension. The solution or suspension containing the active agent contacts the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are arranged at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonators are arranged so that the propagation direction of the bulk acoustic waves generated in the solution or suspension is toward the top of the reservoir, i.e., the surface in contact with the patient's skin. The upper surface of the reservoir has a semi-permeable membrane 40 through which the active agent cannot diffuse freely.

[0069] Preparation of ultra-high frequency acoustic wave resonator:

[0070] An ultra-high frequency acoustic wave resonator was prepared according to a reported method (Zhixin Zhang et al., Small 2017, 13, 1602962-1602980). The ultra-high frequency acoustic wave resonator includes an acoustic wave reflecting layer, a bottom electrode layer, a piezoelectric layer and a top electrode layer arranged in sequence from bottom to top. The overlapping area of ​​the bottom electrode layer, the piezoelectric layer, the top electrode layer and the acoustic wave reflecting layer constitutes a bulk acoustic wave generating area. The top surface of the ultra-high frequency acoustic wave resonator is arranged at the bottom of the PDMS well, and generates bulk acoustic waves toward the top of the well; the area formed by the top surface can be called a bulk acoustic wave action area. The area of ​​the bulk acoustic wave generating area of ​​the ultra-high frequency acoustic wave resonator is about 15000-20000 μm 2 .

[0071] The main steps include:

[0072] The bulk acoustic wave resonator device is fabricated on a 100mm undeposited Si wafer, starting with the deposition of a Bragg reflector, which is made of AlN and SiO2 layers deposited alternately by PVD and CVD, respectively. A sandwich structure including a bottom electrode layer (BE), a piezoelectric layer (AlN), and a top electrode layer (TE) is then deposited and patterned layer by layer. The bottom electrode layer (BE) is made of 600nm thick Mo and deposited on top of the Bragg reflector by PVD, and then the film is patterned by photolithography and plasma etching (e.g., patterned into pentagons or triangles), and then the piezoelectric layer is deposited by PVD, which is a 1000nm thick AlN film on top of the BE with a crystal orientation along the c-axis. In the final step, the resonator is covered with a top electrode layer (TE) of gold deposited using electron beam evaporation followed by wet etching, where the thicknesses of the Au electrode and the underlying Cr adhesive layer are approximately 300nm and approximately 50nm, respectively. The electrode area is configured to be 20,000μm 2, so that the resonator has a characteristic impedance of 50T to match the impedance of the external circuit. The polydimethylsiloxane (PDMS) device wall was prepared by soft lithography.

[0073] The power and time interval of the bulk acoustic wave generated by the ultra-high frequency resonator are adjusted by a signal generator and a power adjustment device.

[0074] Preparation of ex vivo mouse skin

[0075] Take a healthy SD rat weighing about 200 grams, anesthetize it with pentobarbital, carefully cut the abdominal hair with small scissors, shave it with a razor, and avoid scratching the skin, peel off the abdominal skin, lay the skin flat on a glass plate with the stratum corneum facing down, and wipe the subcutaneous fat layer and connective tissue with a saline cotton ball. Rinse it with saline, soak it in saline, and use it on the same day.

[0076] Example 2 Promoting 4000 molecular weight dextran to permeate RC-1000 membrane

[0077] Take a commercial fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 4000 and prepare a 2mg / ml test solution in PBS (pH7.4, gibco, Thermo Fisher Scientific), take 30ul and inject it into the supply pool, cap it with RC-1000 membrane (JMD38, Solarbio), then press the receiving pool tightly on the supply pool across the semipermeable membrane, and inject 300ul of PBS into the receiving pool. The effect of dextran on the permeation of regenerated cellulose membrane was measured under the control and power conditions of activating the ultra-high frequency acoustic resonator to generate bulk acoustic waves without power, and 50ul was sampled at 30, 60, and 90 minutes respectively. The power condition of the ultra-high frequency acoustic resonator was 500mW, frequency 2.58GHz, 0.5S pressure pulse, and 0.5S interval. Each group of experiments was repeated 3 times.

[0078] Determine the content by fluorescence labeling. Take commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) to prepare a 2 mg / ml stock solution, dilute it 12 times in 2 times, and get a 0.0005-2 mg / ml standard solution. Use a fluorescence quantitative microplate reader (SpectraMax Gemini EM) to determine the concentration linear standard curve. Place the experimental sample in the well of the test plate to read the fluorescence value, and determine the concentration of the sample to be tested by referring to the concentration standard curve.

[0079] Method for determining molecular weight. Take commercially available dextran (CM-Dextran, SIGMA) with different molecular weights such as 1000, 5000, 15000, 50000, 200000, 500000 to prepare a 2mg / ml mother solution, and inject it into a liquid phase analysis system (Agilent 1260) with water: methanol = 98:2 as the liquid phase, equipped with a PL aquagel MIXED-D gel column (Agilent ltd.) and a differential refractometer detector, with a flow rate of 1ml / min. Establish a standard curve based on the linear relationship between the peak time and the molecular weight. Inject the experimental sample into the liquid phase analysis system, and determine the molecular weight of the sample from the standard curve by the retention time.

[0080] The results are shown in Table 1, indicating that the effect of special sound waves can promote the penetration of substances with a molecular weight of 4000 through the semipermeable membrane with a molecular weight cutoff greater than 1000.

[0081] Table 1 Results of sonication-assisted permeation of 4000 molecular weight dextran through RC-1000 membrane

[0082]

[0083] -Indicates that the substance was not detected because the concentration was too low.

[0084] Example 3 Promoting 40,000 molecular weight dextran to permeate RC-1000 membrane

[0085] Commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 40,000 was prepared into a 2 mg / ml test solution. The same experimental settings and parameters as in Example 2 were used to conduct the experiment.

[0086] The determination method of content and molecular weight is the same as that of Example 2. The results are shown in Table 2, indicating that the effect of special sound waves can promote the penetration of substances with a molecular weight of 40,000 through a semipermeable membrane with a molecular weight cutoff greater than 1,000.

[0087] Table 2 Results of sonication-assisted permeation of 40,000 molecular weight dextran through RC-1000 membrane

[0088]

[0089] -Indicates that the substance was not detected because the concentration was too low.

[0090] Example 4: Promoting the permeation of 500,000 molecular weight dextran through RC-1000 membrane

[0091] Commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 500,000 was prepared into a 2 mg / ml test solution. The same experimental settings and parameters as in Example 2 were used to conduct the experiment.

[0092] The determination method of content and molecular weight is the same as that of Example 2. The results are shown in Table 3, indicating that the effect of special sound waves can promote the penetration of substances with a molecular weight of 500,000 through a semipermeable membrane with a molecular weight cutoff greater than 1,000.

[0093] Table 3 Results of sonication-assisted permeation of 500,000 molecular weight dextran through RC-1000 membrane

[0094]

[0095] -Indicates that the substance was not detected because the concentration was too low.

[0096] Example 5 Promoting 4000 molecular weight dextran to permeate EC-1000 membrane

[0097] Take the commercial fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 4000 to prepare a 2mg / ml test solution, take 30ul and inject it into the supply pool, cap it with a cellulose ester membrane EC-1000 membrane (MD31, Spectrumlabs), and press the receiving pool tightly on the supply pool, and inject 300ul of PBS into the receiving pool. The effect of dextran on the permeation of cellulose ester membrane was measured under the conditions of no power control and power addition, and 50ul of samples were taken at 30, 60, and 90 minutes respectively. The power addition conditions were 500mW, frequency 2.58GHz, 0.5S pressure pulse, and 0.5S interval. Each group of experiments was repeated 3 times.

[0098] The determination method of content and molecular weight is the same as that of Example 2. The results are shown in Table 4, indicating that the effect of special sound waves can promote the penetration of substances with a molecular weight of 4000 through the semipermeable membrane of cellulose ester membrane with a molecular weight cutoff greater than 1000.

[0099] Table 4 Results of sonication-assisted permeation of 4000 molecular weight dextran through EC-1000 membrane

[0100]

[0101] -Indicates that the substance was not detected because the concentration was too low.

[0102] Example 6 Promoting 500,000 molecular weight dextran to permeate RC-1000 membrane

[0103] A 2 mg / ml test solution was prepared with commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 500,000. The same experimental settings and parameters as in Example 5 were used to conduct the experiment.

[0104] The determination methods of content and molecular weight are the same as those in Example 2. The results are shown in Table 6, indicating that the effect of special sound waves can promote the penetration of substances with a molecular weight of 500,000 through the semipermeable membrane of cellulose ester membrane with a molecular weight cutoff greater than 1,000.

[0105] Table 5 Results of sonication-assisted permeation of 500,000 molecular weight dextran through EC-1000 membrane

[0106]

[0107] -Indicates that the substance was not detected because the concentration was too low.

[0108] Example 7 Insulin-Promoting RC-1000 Membrane

[0109] Take commercially available insulin injection (300IU / 3ml, Novolin 30R, Novo Nordisk, Denmark) 30ul and inject it into the liquid supply pool connected to the device, cap it with RC-1000 membrane (JMD38, Solarbio), and press the receiving pool tightly across the semipermeable membrane on the liquid supply pool, and inject PBS 300ul in the receiving pool. The transdermal effect of insulin is measured under the conditions of not adding power to activate the ultrahigh frequency acoustic resonator and adding power, respectively, as a control and test sample. 50ul is sampled successively at 30, 60, and 90 minutes, and the power condition is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Each group of experiments is repeated 3 times.

[0110] Method for determination of insulin content: octadecylsilane bonded silica gel is used as filler (5-10 μm); 0.2 mol / L sulfate buffer (take 28.4 g of anhydrous sodium sulfate, dissolve it in water, add 1.7 ml of phosphoric acid, adjust the pH value to 2.3 with ethanolamine, and add water to 1000 ml)-acetonitrile (74:26) is used as mobile phase; column temperature is 40°C; detection wavelength is 214 nm. Take 20 μl of system suitability solution (take insulin reference substance, dissolve it in 0.01 mol / L hydrochloric acid solution and dilute it to make a solution containing about 40 units per 1 ml, and leave it for at least 24 hours), inject it into liquid chromatograph, record the chromatogram, the separation between insulin peak and A21 deaminized insulin peak (relative retention time with insulin peak is about 1.2) should be not less than 1.8, and the tailing factor should be not more than 1.8. Accurately measure 20 μl and inject it into liquid chromatograph, record the chromatogram; take an appropriate amount of insulin reference substance and determine it in the same way. The content is calculated by the external standard method using the sum of the insulin peak area and the A21 desamino insulin peak area.

[0111] The results are shown in Table 7, indicating that the effect of special sound waves can promote the permeation of insulin through the semipermeable membrane of regenerated cellulose membrane with a molecular weight cutoff greater than 1000.

[0112] Table 6 Results of the special sonic wave insulin permeation RC-1000 membrane

[0113]

[0114] Example 8 Effect of Ultrahigh Frequency Bulk Acoustic Wave Power Change on Insulin Permeable RC-1000 Membrane

[0115] The experiment was conducted using the same experimental settings and parameters as in Example 7 to test the effect of different powers of activating the ultrahigh frequency acoustic wave resonator. The powers were 500mW, 800mW, 1000mW, and 2000mW, respectively. Each group of experiments was repeated 3 times. The method for determining the insulin content was the same as in Example 7, and the results are shown in Table 8.

[0116] Table 7 Effects of different power ultrasonic waves on insulin-promoting RC-1000 membrane

[0117]

[0118]

[0119] The results show that within a certain range, as the power increases, the penetration-enhancing effect of the special sound waves increases synchronously.

[0120] Example 9 Effect of Multi-Chip Combination on Insulin Permeability RC-1000 Membrane

[0121] The same experimental settings and parameters as in Example 7 were used to test the effect of using multiple ultra-high frequency acoustic wave resonators at the bottom of the same liquid supply pool. 1, 2, 4, and 8 ultra-high frequency acoustic wave resonators were set on the circuit board at the bottom of the liquid supply pool. Each group of experiments was repeated 3 times. The results are shown in Table 10.

[0122] Table 8 The results of the effects of different number of chips combined with special sound waves on insulin-promoting RC-1000 membrane

[0123]

[0124] The results show that as the amount of special sound wave nano-microchips increases, the penetration-enhancing effect of special sound waves increases synchronously.

[0125] Example 10 Promoting the penetration of 4000 molecular weight dextran into rat skin

[0126] Take a commercial fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 4000 to prepare a 2mg / ml test solution, take 30ul and inject it into the supply pool, cap it with the SD rat ex vivo skin prepared according to the method described in Example 1, and press the receiving pool tightly across the SD rat ex vivo skin on the supply pool, and inject 300ul of PBS into the receiving pool. The effect of dextran on rat skin penetration was measured under the control and power conditions of not adding power to activate the ultra-high frequency acoustic resonator to generate body acoustic waves. Samples of 50ul were taken at 30, 60, and 90 minutes, respectively, and the power conditions were 500mW, frequency 2.58GHz, 0.5S pressure pulse, and 0.5S interval. Each group of experiments was repeated 3 times.

[0127] The content and molecular weight were determined in the same manner as in Example 2. The results are shown in Table 9, which show that the effect of special sound waves can promote the penetration of dextran with a molecular weight of 4000 through the rat skin.

[0128] Table 9 Results of the ultrasonic wave-assisted permeation of 4000 molecular weight dextran into the skin of SD rats

[0129]

[0130] -Indicates that the substance was not detected because the concentration was too low.

[0131] Example 11 Promoting the penetration of 40,000 molecular weight dextran into rat skin

[0132] Commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 40,000 was prepared into a 2 mg / ml test solution. The same experimental settings and parameters as in Example 10 were used to conduct the experiment.

[0133] The content and molecular weight were determined in the same manner as in Example 2. The results are shown in Table 10, which show that the effect of special sound waves can promote the penetration of dextran with a molecular weight of 40,000 through the rat skin.

[0134] Table 10 Results of the ultrasonic wave-assisted permeation of 40,000 molecular weight dextran into the skin of SD rats

[0135]

[0136]

[0137] -Indicates that the substance was not detected because the concentration was too low.

[0138] Example 12 Promotes the penetration of 500,000 molecular weight dextran into rat skin

[0139] A 2 mg / ml test solution was prepared with commercially available fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 500,000. The same experimental settings and parameters as in Example 10 were used to conduct the experiment.

[0140] The determination method of content and molecular weight is the same as that of Example 2. The results are shown in Table 11. The results show that the effect of special sound waves can promote the penetration of dextran with a molecular weight of 500,000 through rat skin.

[0141] Table 11 Results of the ultrasonic wave-assisted penetration of 500,000 molecular weight dextran into rat skin

[0142]

[0143] -Indicates that the substance was not detected because the concentration was too low.

[0144] Example 13 Promoting insulin permeation through rat skin

[0145] 30ul of commercially available insulin injection (300IU / 3ml, Novolin 30R, Novo Nordisk, Denmark) was injected into the liquid supply pool connected to the device, and the SD rat ex vivo skin prepared according to the method described in Example 1 was used to cap the top, and the receiving pool was tightly pressed on the liquid supply pool, and 300ul of PBS was injected into the receiving pool. The effect of dextran penetrating rat skin was measured under the control of not adding power to activate the ultrahigh frequency acoustic wave resonator to generate body acoustic waves and the conditions of adding power, respectively. 50ul of samples were taken at 30, 60, and 90 minutes, respectively, and the power conditions were 500mW, frequency 2.58GHz, 0.5S pressure pulse, and 0.5S interval. Each group of experiments was repeated 3 times.

[0146] The method for determining the insulin content was the same as in Example 7. The results are shown in Table 12, indicating that the effect of special sound waves can promote the penetration of insulin through rat skin.

[0147] Table 12 Results of the special sound wave to promote insulin permeation into the skin of SD rats

[0148]

[0149]

[0150] Example 14 Effect of power variation on insulin permeation into rat skin

[0151] The experiment was conducted using the same experimental settings and parameters as in Example 13 to test the effect of different powers of activating the ultrahigh frequency acoustic resonator. The powers were 500mW, 800mW, 1000mW, and 2000mW, respectively. Each group of experiments was repeated 3 times. The method for determining the insulin content was the same as in Example 7, and the results are shown in Table 13.

[0152] Table 13 Effects of different power sound waves on the skin of insulinotropic rats

[0153]

[0154] The results show that within a certain range, as the power increases, the penetration-enhancing effect of the special sound waves increases synchronously.

[0155] Example 15 Effect of multi-chip combination on insulin permeation into rat skin

[0156] The experiment was conducted using the same experimental settings and parameters as in Example 13 to test the effect of using multiple ultra-high frequency acoustic wave resonators at the bottom of the same liquid supply pool. 1, 2, 4, and 8 ultra-high frequency acoustic wave resonators were set on the circuit board at the bottom of the liquid supply pool, respectively. Each group of experiments was repeated 3 times. The results are shown in Table 14.

[0157] Table 14 The results of the effects of different number of chips combined with special sound waves on insulin-promoting rat skin

[0158]

[0159] The results show that as the amount of special sound wave nano-microchips increases, the penetration-enhancing effect of special sound waves increases synchronously.

[0160] Example 16: Promoting the permeation of 40,000 molecular weight dextran through EC-1000 membrane into rat skin

[0161] Take a commercial fluorescent labeled dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 40,000 to prepare a 2mg / ml test solution, take 30ul and inject it into the supply pool, cap it with RC-1000 membrane (JMD38, Solarbio), and then cover it with the SD rat ex vivo skin prepared according to the method described in Example 1, then press the receiving pool tightly across the SD rat ex vivo skin on the supply pool, and inject 300ul of PBS into the receiving pool. The effect of dextran on rat skin penetration was measured under the control and power conditions of not adding power to activate the ultra-high frequency acoustic resonator to generate body acoustic waves, and 50ul was sampled at 30, 60, and 90 minutes respectively. The power condition of the ultra-high frequency acoustic resonator was 500mW, frequency 2.58GHz, 0.5S pressure pulse, and 0.5S interval. Each group of experiments was repeated 3 times.

[0162] The content and molecular weight were determined in the same manner as in Example 2. The results are shown in Table 15, indicating that the effect of the special sound wave can promote the substance with a molecular weight of 40,000 to pass through the rat skin after passing through the semipermeable membrane with a molecular weight cutoff greater than 1,000.

[0163] Table 15 Results of sonication-induced permeation of 40,000 molecular weight dextran through RC-1000 membrane and rat skin

[0164]

[0165] -Indicates that the substance was not detected because the concentration was too low.

[0166] Example 17 Insulin permeation through semipermeable membrane in rats and the effect of ultrasound frequency

[0167] Get commercially available insulin injection (300IU / 3ml, Novolin 30R, Novo Nordisk, Denmark) 30ul is injected into the liquid supply pool connected to the device, capped with RC-1000 film (JMD38, Solarbio), then covered with the SD rat ex vivo skin prepared according to the method for recording in Example 1, then the receiving pool is tightly pressed on the liquid supply pool across the SD rat ex vivo skin. The transdermal effect of insulin is measured on the condition of no power and power respectively, which is respectively control and test sample. 50ul is sampled successively at 30, 60, 90 minutes, and the power condition is 500mW, frequency 1.31GHz, 1.82GHz, 2.58GHz, 2.84GHz, 3.54GHz, 0.5S pressure pulse, 0.5S interval. Each group of experiments is repeated 3 times. The insulin content determination method is with embodiment 7, and the result is as shown in table 16.

[0168] Table 16 The results of the effects of different frequency special sound waves on insulin-promoting rat skin

[0169]

[0170]

[0171] Example 18 Evaluation of insulinotropic transdermal efficacy in rats

[0172] Male SD rats weighing about 200g were used, with free access to water and food, and the bedding was changed every day. Before the experiment began, all rats were fed adaptively under the research conditions for 3 days, marked and weighed, and the STZ (streptozotocin) dose required for each rat to establish the diabetes model was calculated based on the dosage of 45mg / kg. 100mg STZ was dissolved in citric acid buffer (pH=4.0, sterilized by membrane), and the corresponding dose of STZ solution was injected into the tail vein according to the weight of different SD rats. After 4 days, all rats were injected intravenously to draw blood for blood sugar testing. The average blood sugar was above 16.7mmol / L, indicating that the diabetes model was successfully established.

[0173] Take commercially available insulin injection (300IU / 3ml, Novolin 30R, Novo Nordisk, Denmark) 300ul is injected into the liquid supply pool, tightly sealed with RC-1000 film (JMD38, Solarbio), the liquid supply pool is fixed to the rat abdomen anesthetized with ether, and the RC-1000 film of the liquid supply pool contacts the abdomen. The transdermal effect of insulin is measured under the conditions of not adding power to activate the ultra-high frequency acoustic wave resonator to produce body acoustic waves and adding power, respectively, for control and test sample. The power adding condition is 500mW, 2.58GHz, 0.5S pressure pulse, 0.5S interval, and release for 90 minutes. Detect the change of blood sugar at 2, 4, 6, 8, 10, 12 hours, compare with the synchronous blood sugar of the normal anesthesia non-administration group, and set up the insulin group of equal amount of intravenous injection to positive control separately. Each group of experiments is repeated 3 times. The result is as shown in Table 17.

[0174] Table 17 In vivo experimental results of special sound waves promoting insulin permeation through rat skin

[0175]

[0176]

[0177] The experiment found that under the same conditions, compared with the control group without power activation of the ultra-high frequency acoustic wave resonator, the power group can significantly reduce the blood sugar content in the animal body, indicating that the transdermal effect is significant. Compared with the intravenous injection group, the power group has the effect of continuous drug release, and can maintain a significant hypoglycemic effect within 8 hours, while the intravenous injection group reaches the maximum hypoglycemic effect after 2 hours, and loses its effective hypoglycemic effect after 4 hours. It can be seen that the hypoglycemic effect of the special acoustic wave transdermal promotion method and device of the present invention is highly efficient and long-lasting, and has obvious advantages over the prior art.

[0178] The present invention provides a new method and device for transdermal delivery of biologically active substances, especially for transdermal delivery of drug molecules that are difficult or impossible to penetrate the skin, by using an ultra-high frequency resonator to generate body acoustic waves. The inventor unexpectedly found that the body acoustic waves generated by the ultra-high frequency resonator can effectively pass small molecule compounds and proteins through semi-permeable membranes, and even through the skin of animals, thereby providing a method and device for safely and conveniently delivering small molecule chemical drugs, polypeptide drugs, and biological drugs such as antibodies and vaccines. The inventor has also solved a method for preparing a drug delivery composition and device from an active substance present in a liquid, including encapsulating it with a translucent film.

[0179] Although the exemplary embodiments of the present invention and their advantages have been described in detail, it should be understood that various changes, substitutions and modifications may be made to these embodiments without departing from the spirit of the present invention and the scope of protection defined by the appended claims. For other examples, it should be readily understood by those skilled in the art that the order of the process steps may be changed while maintaining the scope of protection of the present invention.

[0180] In addition, the scope of application of the present invention is not limited to the processes, mechanisms, manufactures, material compositions, means, methods and steps of the specific embodiments described in the specification. From the disclosure of the present invention, it will be easily understood by those skilled in the art that the processes, mechanisms, manufactures, material compositions, means, methods or steps that currently exist or will be developed in the future, which perform substantially the same functions as the corresponding embodiments described in the present invention or obtain substantially the same results, can be applied according to the present invention. Therefore, the claims attached to the present invention are intended to include these processes, mechanisms, manufactures, material compositions, means, methods or steps within their scope of protection.

Claims

1. A device for administering an active agent to a patient via transdermal delivery, characterized in that It includes a reservoir containing a solution or suspension containing a biologically active agent; One or more ultra-high frequency bulk acoustic wave resonators are arranged at the bottom of the reservoir, and the one or more ultra-high frequency bulk acoustic wave resonators are arranged to generate bulk acoustic waves with a frequency of 0.5-50 GHz in the solution or suspension, wherein the propagation direction of the generated bulk acoustic waves is toward the top of the reservoir, and the surface of the top of the reservoir is in contact with the patient's skin; The bulk acoustic waves induce the bioactive agent in the solution or suspension in the reservoir to flow in the direction of acoustic wave propagation to pass through the skin and enter the interior of the skin.

2. The device according to claim 1, characterized in that The upper surface of the reservoir has a semipermeable membrane.

3. The device according to claim 1, characterized in that The reservoir further has an opening or hole suitable for adding a solution or suspension, or loading a packaging bag containing a solution or suspension.

4. The device according to claim 1, characterized in that It also includes a housing, and the reservoir is detachably connected to the housing.

5. The device according to claim 1, characterized in that The bioactive agent is a small molecule compound, a polypeptide, a protein, an oligonucleotide, a nucleic acid or a polysaccharide.

6. The device according to claim 1, characterized in that The molecular weight of the bioactive agent is 200-1,000,000 Daltons.

7. The device according to claim 1, characterized in that The ultra-high frequency acoustic wave resonator is a thin film bulk acoustic wave resonator or a solid-state assembly type resonator.

8. The device according to claim 1, characterized in that The depth of the reservoir is 0.1-20 mm.

9. The device according to claim 1, characterized in that The area of ​​the bulk acoustic wave generation region of the ultra-high frequency acoustic wave resonator is 1000-50000 μm 2 .

10. The device according to claim 1, characterized in that The power of the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator is 0.1-50W.

11. A transdermal drug delivery device, characterized in that: It includes a reservoir containing a solution or suspension containing a biologically active agent; One or more ultra-high frequency bulk acoustic wave resonators are detachably disposed at the bottom of the reservoir, wherein the one or more ultra-high frequency bulk acoustic wave resonators are configured to generate bulk acoustic waves with a frequency of 0.5-50 GHz in the solution or suspension, wherein the generated bulk acoustic waves propagate toward the top of the reservoir, and the surface of the top of the reservoir contacts the patient's skin; The bulk acoustic waves induce the bioactive agent in the solution or suspension in the reservoir to flow in the direction of acoustic wave propagation to pass through the skin and enter the interior of the skin.

12. The transdermal drug delivery device according to claim 11, wherein The upper surface of the reservoir has a semipermeable membrane.

13. The transdermal drug delivery device according to claim 11, wherein The reservoir further has an opening or hole suitable for adding a solution or suspension, or loading a packaging bag containing a solution or suspension.

14. The transdermal drug delivery device according to claim 11, wherein The molecular weight of the bioactive agent is 200-1,000,000 Daltons.

15. The transdermal drug delivery device according to claim 11, wherein The bioactive agent is a small molecule compound, a polypeptide, a protein, an oligonucleotide, a nucleic acid or a polysaccharide.

16. The transdermal drug delivery device according to claim 11, wherein The ultra-high frequency resonator has a circuit for receiving a pulse voltage signal.

17. The transdermal drug delivery device according to claim 11, wherein The ultra-high frequency acoustic wave resonator is a thin film bulk acoustic wave resonator or a solid-state assembly type resonator.

18. The transdermal drug delivery device according to claim 11, wherein The thickness of the reservoir is 0.1-20 mm.

19. The transdermal drug delivery device according to claim 11, wherein: The area of ​​the bulk acoustic wave generation region of the ultra-high frequency acoustic wave resonator is 1000-50000 μm 2 .

20. The transdermal drug delivery device according to claim 11, wherein The power of the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator is 0.1-50W.

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