WO2020249013A1 - 透皮给药方法、制剂和装置 - Google Patents

透皮给药方法、制剂和装置 Download PDF

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Publication number
WO2020249013A1
WO2020249013A1 PCT/CN2020/095399 CN2020095399W WO2020249013A1 WO 2020249013 A1 WO2020249013 A1 WO 2020249013A1 CN 2020095399 W CN2020095399 W CN 2020095399W WO 2020249013 A1 WO2020249013 A1 WO 2020249013A1
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Prior art keywords
acoustic wave
ultra
bulk acoustic
resonator
high frequency
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PCT/CN2020/095399
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English (en)
French (fr)
Inventor
段学欣
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海得摩尔医药科技有限公司
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Publication of WO2020249013A1 publication Critical patent/WO2020249013A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy

Definitions

  • the invention relates to a drug release method and device. More specifically, the present invention relates to a method and device for generating a bulk acoustic wave using an ultra-high frequency resonator to promote transdermal drug release.
  • the method of the present invention can realize the transdermal penetration of materials that are difficult or impermeable to the skin, including but not limited to small molecule chemical drugs, polypeptide drugs, and biologically active materials such as antibodies and vaccines.
  • the skin covers the surface of the human body to prevent foreign substances from entering the human body and has an important protective function.
  • the skin is tightly combined with the epidermis and dermis.
  • the epidermis is composed of stratified squamous epithelium, from the shallower to the deeper, the stratum corneum, the transparent layer, the granular layer and the germinal layer.
  • the stratum corneum is composed of multiple layers of keratinized epithelial cells. It is inanimate and impermeable. It is the main barrier for the absorption of foreign substances through the skin.
  • the dermis is composed of dense connective tissue, which is rich in collagen fibers, elastic fibers and reticular fibers, which are intertwined into a network, which makes the skin more elastic and tough.
  • transdermal refers to the release of active agents (such as therapeutic agents such as drugs, or immunologically active agents such as vaccines) through the skin to local tissues or the systemic circulatory system, basically without cutting or piercing the skin. For example, cutting with a scalpel or piercing the skin with a hypodermic needle.
  • active agents such as therapeutic agents such as drugs, or immunologically active agents such as vaccines
  • the advantages of the transdermal drug delivery system are reflected in: drug absorption is not affected by factors such as pH, food, and transit time in the digestive tract; avoids the liver first-pass effect; overcomes adverse reactions caused by excessive blood concentration due to excessive absorption; sustainable Control the speed of drug delivery, flexible drug delivery, etc.
  • the epidermis especially the stratum corneum, is the main barrier for drugs to enter the body. Studies have found that only a few drugs have excellent skin permeability, and most drugs cannot easily pass through the effective and selective barrier of human skin.
  • the technologies for dynamically opening the dense structure of the stratum corneum to achieve transdermal drug delivery mainly include chemical penetration enhancement and physical penetration enhancement (conductivity, microneedle) and so on.
  • Chemical penetration enhancement is mainly achieved by a substance that can reversibly change the barrier function of the skin stratum corneum without damaging any active cells, enhance the ability of drug penetration, and increase the amount of drug penetration.
  • the advantage of chemical penetration enhancement is that it can be integrated with pharmaceutical preparations, but when the dosage is large or for a long time, it will cause skin irritation, pain and other irritation. Compatibility with the pharmaceutical ingredients is also an important factor restricting its application.
  • Microneedle penetration enhancement is to apply a transdermal patch consisting of tens to hundreds of hollow or solid microneedles to the skin, penetrate the stratum corneum barrier and create tiny channels in the epidermis. The drugs enter the systemic circulation through the tiny channels. Promote the penetration of drugs to specific parts, suitable for macromolecular drugs (such as peptides, proteins and vaccines with low skin permeability).
  • Electroporation technology means that under the action of instantaneous high-voltage pulse current, the disordered structure of the lipid bilayer increases to form short-lived and reversible hydrophilic pores, thereby improving the permeability of cell and tissue membranes, but it depends on charged devices and energy The characteristics lead to limited promotion.
  • Laser technology is a physical penetration enhancement technology that uses the photo-mechanical wave formed by laser impact on the skin to promote the transdermal absorption of macromolecular drugs.
  • Magnetic field introduction to promote penetration is a physical technology that uses magnetic fields to increase the permeability of drugs through the skin.
  • Thermal perforation is a technique that uses pulse heating to form hydrophilic channels in the stratum corneum to increase skin permeability. The complexity and high cost of magnetic field introduction and thermal perforation technology are problems that need to be broken.
  • cavitation refers to the process of formation, expansion, contraction and disintegration of gas bubbles in the propagation of ultrasonic waves in the medium.
  • the existing research results show that the lower the frequency, the better the cavitation effect. Therefore, the use of low-frequency (especially 20KHz) ultrasound and the use of some surface active substances to reduce the surface tension of the liquid medium are to improve the cavitation effect and increase the drug permeability. The main direction.
  • the art also needs effective and safe transdermal drug delivery methods and devices.
  • the present invention provides a new method and device for transdermal administration of biologically active substances by using ultra-high frequency resonators to generate bulk acoustic waves, especially for drug molecules that are difficult or impermeable to the skin.
  • the method provided by the invention can effectively and safely deliver small molecule chemical drugs, polypeptide drugs, and biological drugs such as antibodies and vaccines.
  • the present invention provides a method for administering a bioactive agent to a patient through transdermal release, the method comprising:
  • a reservoir containing a bioactive agent
  • the reservoir is used to hold a solution, suspension or gel containing the active agent
  • transdermal refers to the purpose of local or systemic treatment, allowing the drug to enter and/or pass through the skin for release.
  • Patients refer to humans or other animals, including but not limited to other primates such as chimpanzees and other apes and monkeys; farm animals such as cows, sheep, pigs, goats and horses; domestic animals such as dogs and cats; laboratories Animals include rodents such as mice, rats and guinea pigs; birds, including domestic, wild and play birds such as chickens, turkeys and other galliformes, ducks, and geese.
  • primates such as chimpanzees and other apes and monkeys
  • farm animals such as cows, sheep, pigs, goats and horses
  • domestic animals such as dogs and cats
  • laboratories Animals include rodents such as mice, rats and guinea pigs; birds, including domestic, wild and play birds such as chickens, turkeys and other galliformes, ducks, and geese.
  • a biologically active agent refers to a composition containing an active agent or drug substance or mixture, which is pharmacologically effective when administered to a patient in a therapeutically effective amount.
  • bioactive agents include, but are not limited to, small molecular weight compounds, polypeptides, proteins, oligonucleotides, nucleic acids, and polysaccharides.
  • the molecular weight of the bioactive agent ranges from 200 to 1,000,000 Daltons.
  • the bioactive agent can also be delivered by attaching to a carrier.
  • the carrier can be any solid substrate used in biotechnology for immobilization.
  • Specific supports include silica, glass, inorganic supports such as metal nanoparticles or alumina, and organic supports such as polymer supports (e.g., polystyrene).
  • the solid support is polymer particles, especially polymer particles, with a diameter of 50 nm to 500 ⁇ m, for example, 100 nm to 100 ⁇ m.
  • biologically active agents include, but are not limited to, Luteinizing Hormone Releasing Hormone (LHRH); LHRH analogues (e.g. goserelin, leuprolide, buserelin, triptorelin, gonarelin And napfarelin, urogonadotropins (Follicle Stimulating Hormone (FSH) and LH); Vasopressin; Desmopressin; Corticotropin (ACTH); ACTH analogs such as ACTH (1-24); Calcitonin; Vasopressin; Deamino[Val4, D-Arg8] Arginine Vasopressin; Alpha Interferon; Beta Interferon; Gamma Interferon; Erythropoietin (EPO); Granulocyte Macrophage Colony Stimulation Factor (GM-CSF); Granulocyte Colony Stimulating Factor (G-CSF); Interleukin-10 (IL-10); Glucagon; Growth Factor
  • the method of the present invention is particularly suitable for pharmaceutically active agents that are difficult or impermeable to the skin.
  • larger active agents such as polypeptides or proteins.
  • the protein may include cytokines, hormones, vitamins, surface receptors, haptens, antigens, antibodies, enzymes, growth factors, recombinant proteins, toxins, and fragments and combinations thereof.
  • small-molecule drugs that are unsuitable or unable to pass through commonly used transdermal preparations due to physical properties such as hydrophobicity.
  • the active agent is present in a solution or suspension or gel.
  • the solution or suspension or gel is in contact with the skin of the patient.
  • the solution or suspension or gel is in contact with the skin of the patient through a semipermeable membrane.
  • the solution or suspension or gel can be directly added to the reservoir of the device of the present invention, and the upper surface of the reservoir is sealed with a semi-permeable membrane.
  • the solution or suspension or gel can also be provided in a pre-packaged form.
  • the encapsulated material includes a semi-permeable membrane.
  • the solution, suspension or gel contains various solvents in which the bioactive agent is soluble.
  • the solvent contained in the solution or suspension or gel is an aqueous solvent, such as water.
  • the solution may also include non-aqueous solvents such as ethanol, chloroform, ether, propylene glycol, polyethylene glycol and the like.
  • the solution, suspension or gel may also contain inert fillers; penetration enhancers; excipients and other drugs or conventional transdermal devices known in the art Components.
  • the gel that can be used in the method of the present invention can be various natural or polymer gels, such as hydrogels.
  • Hydrogels can be naturally occurring (such as agarose, dextran, chitin, cellulose-based compounds, starch, derivative starch, etc.) or synthetically prepared or modified (such as polyethylene glycol PEG) .
  • Hydrogel is a substance that contains a three-dimensional network of macromolecules, which makes it swell when there is water, and shrink when there is water shortage (or by reducing the amount of water), but is insoluble in water. The cross-links between adjacent macromolecules result in the water insolubility of the hydrogel.
  • hydrogel dry state of the macromolecular material suitable for the present invention
  • xerogel dry state of the macromolecular material suitable for the present invention
  • hydrogel hydrated state
  • the term “hydrogel” “Refers to macromolecular materials whether anhydrous or hydrated.
  • the most characteristic feature of hydrogels is that the material retains its regular shape regardless of whether it is dehydrated or hydrated. Therefore, if the hydrogel is approximately spherical in the dehydrated state, it will be spherical in the hydrated state.
  • the hydrogel used in the present invention is preferably a water-based hydrogel because of its high water content and biocompatibility.
  • the polymer in the hydrogel used in the present invention includes but is not limited to hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC ), hydroxyethyl methyl cellulose (HEMC), ethyl hydroxyethyl cellulose (EHEC), carboxymethyl cellulose (CMC), poly (vinyl alcohol), poly (ethylene oxide), poly (2 -Hydroxyethyl methacrylate), poly(n-vinylpyrrolidone) and poloxamer.
  • the preferred polymer material is a cellulose derivative.
  • the active agent can be combined with the hydrogel in this way: the active agent diffuses into the macromolecular network in water, and then the macromolecular material is dried to fix the active agent in the hydrogel.
  • the combination of the active agent and the hydrogel may be uniformly dispersed and completely absorbed in the resulting hydrogel, or partially dispersed in only a part of the hydrogel particles.
  • Other methods or alternative methods are that the combination of the active agent and the hydrogel is due to the formation of ionic or covalent bonds between the two components, and the active agent is mainly contained in the hydrogel matrix or with the hydrogel structure Surface bonding (such as bonding).
  • 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 membrane, parchment semipermeable membrane, polymer Semi-permeable membranes such as cellulose ester membranes, regenerated cellulose membranes, polypropylene membranes, etc.
  • the bioactive agent may be present in the solution, suspension or gel in any possible content.
  • the appropriate content can be obtained by referring to transdermal preparations known in the art, or by testing by known methods.
  • the method of the present invention can adjust the amount of transdermal active agent by controlling various parameters of the ultrasonic wave generated by the ultra-high frequency acoustic wave resonator, it is possible to detect and select a suitable solution, suspension or gel through experiments.
  • the content is to ensure that the active agent is administered to the patient in a therapeutically effective and safe amount.
  • a reservoir containing a bioactive agent is used.
  • the reservoir is suitable for holding solutions, suspensions or gels.
  • the solution or suspension of the active agent can be directly added to the reservoir, and then the upper surface of the reservoir is sealed with a semi-permeable membrane, or it can be provided in a pre-encapsulated form.
  • the packaging material can be a semi-permeable membrane or the like.
  • the reservoir has four frames for holding solutions or suspensions or gels.
  • the reservoir has two to four frames or card slots, a packaging bag for containing a solution or suspension, or a gel sheet or block.
  • the reservoir is the gel, such as gel sheet and gel block.
  • a UHF acoustic wave resonator is used to generate UHF (about 0.5-50 GHz) bulk acoustic waves in the solution.
  • Particles such as bioactive agents
  • inertial lift force generated by laminar flow
  • acoustic radiation force caused by sound wave attenuation
  • Acoustic radiation force acoustic radiation force caused by sound wave attenuation
  • the bulk acoustic wave triggers the particles in the solution to flow in the direction of the sound wave, which can penetrate the skin and enter the skin. Cause irreversible damage to the skin.
  • the ultra-high frequency acoustic wave resonator used in the present invention can generate ultra-high frequency (about 0.5-50 GHz) vibration and induce bulk acoustic waves of corresponding frequencies in the solution.
  • the ultra-high frequency acoustic resonator is a thin film bulk acoustic resonator (FBAR) or a solid state assembled resonator (SMR), preferably a solid state assembled resonator.
  • the ultra-high frequency acoustic resonator is a thickness stretching vibration mode acoustic resonator, and the piezoelectric material thin film layer is grown in the vertical direction, and it is excited by the d33 piezoelectric coefficient coupling vertical electric field. vibration.
  • the ultra-high frequency acoustic wave resonator used in the present invention can generate a localized acoustic current at the interface between the device and the liquid without the aid 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 order 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 bulk acoustic wave generation area.
  • the top surface of the UHF acoustic resonator is arranged on the wall of the container containing the liquid (for example, the bottom of the reservoir of the present invention), and a bulk acoustic wave whose propagation direction is perpendicular to the wall is generated to the opposite wall;
  • the area formed by the top surface can be referred to as a bulk acoustic wave action area.
  • the thickness of the piezoelectric layer of the ultra-high frequency acoustic resonator of the present invention ranges from about 1 nm to 2 um.
  • the frequency of the ultra-high frequency acoustic resonator of the present invention is about 0.5-50 GHz, preferably about 1-10 GHz.
  • the shape of the acoustic wave action area can be any shape.
  • the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator has a width of about 50-300 ⁇ m, for example, about 70-150 ⁇ m.
  • the area of the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator is about 1000-50000 ⁇ m 2 , preferably about 5000-20000 ⁇ m 2 .
  • the distance between the UHF acoustic resonator and the patient's skin is about 0.1-20 mm, preferably 0.5-15 mm , Most preferably about 1-10mm.
  • the inventor of the present application unexpectedly discovered that when the distance between the UHF acoustic resonator and the patient’s skin is about 0.1-20 mm, the active agent can be effectively penetrated through the skin while maintaining the activity of biomolecules such as proteins. , And high transdermal efficiency.
  • the height of the reservoir is about 0.1-20 mm, preferably 0.5-15 mm, most preferably about 1-10 mm.
  • the upper surface of the reservoir is in contact with the patient's skin, so the height of the reservoir is equivalent to the distance between the UHF acoustic resonator and the patient's skin.
  • the transdermal efficiency of the bioactive agent 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 through a power adjusting device.
  • the output power of the power adjusting device is about 0.1-50W, preferably 0.2-10W, more preferably 0.5-5W.
  • the bulk acoustic wave generated by the ultra-high frequency acoustic wave resonator is driven by the signal of the high frequency signal generator.
  • the pulse voltage signal driving the resonator can be driven by pulse width modulation, which can generate any desired waveform, such as sine wave, square wave, sawtooth wave or triangle wave.
  • Pulse voltage signals can also have amplitude modulation or frequency modulation start/stop capabilities to start or eliminate bulk acoustic waves.
  • a device for administering the active agent to a patient through transdermal release includes:
  • a reservoir containing the active agent is used to contain a solution or suspension or gel containing the active agent; in one of the embodiments, the reservoir is the gel itself;
  • One or more ultra-high-frequency bulk acoustic wave resonators arranged at the bottom of the reservoir, and the one or more ultra-high-frequency bulk acoustic wave resonators generate a frequency of about 0.5-50 GHz in the solution or suspension Body acoustic wave.
  • the solution or suspension containing the active agent is in contact with 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 resonator is arranged such that the propagation direction of the bulk acoustic wave generated in the solution or suspension is toward the top of the reservoir, that is, the surface in contact with the patient's skin.
  • the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot diffuse freely.
  • the outer surface of the semipermeable membrane may also have a peelable closure membrane, which can be peeled off before use (in contact with the patient's skin).
  • the device includes a gel containing an active agent; the gel is usually in contact with the patient's skin on its top, that is, its upper surface;
  • One or more ultra-high frequency bulk acoustic wave resonators in contact with the bottom of the gel, and the one or more ultra-high frequency bulk acoustic wave resonators are arranged in the gel to generate bulk acoustic waves with a frequency of about 0.5-50 GHz.
  • the propagation direction of the bulk acoustic wave generated by the UHF bulk acoustic wave resonator in the gel is toward the top of the gel, that is, the surface in contact with the patient's skin.
  • the gel is a hydrogel, especially a water-based hydrogel.
  • the upper surface of the gel has a semipermeable membrane through which the active agent cannot diffuse freely.
  • the outer surface of the semipermeable membrane may also have a peelable closure membrane, which can be peeled off before use (in contact with the patient's skin).
  • the upper surface of the gel also has a skin adhesion layer, which may comprise a polymer film selected from the group consisting of polyacrylic acid, chitosan, pectin, hydroxypropyl cellulose (HPC ), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), or other skin adhesive polymers.
  • the gel itself contains a skin adhesive polymer.
  • the reservoir has an opening or an opening, which is suitable for adding a solution or suspension or gel, or for loading a packaging bag containing a solution or suspension or gel, or for loading a gel ( Gel block or gel sheet, etc.).
  • the device further includes a housing, and the reservoir is detachably connected to the housing.
  • the housing has a mechanism suitable for being fixed to the human or animal body so that the upper surface of the storage keeps in contact with the skin, such as a buckle.
  • the UHF resonator in the device has a circuit for receiving pulsed voltage signals.
  • the ultra-high frequency resonator has a circuit and an interface for receiving connection with an external high-frequency signal generator, and the interface is provided on the device housing.
  • the UHF resonator has a circuit that receives radio frequency signals.
  • the device further includes a timed emission signal system to excite the UHF bulk acoustic wave resonator within a specified time or time period.
  • the height of the reservoir (the distance from the bottom to the top, such as the semipermeable membrane to the top) is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1-10 mm.
  • the upper surface of the reservoir is in contact with the patient's skin, so the height of the reservoir is equivalent to the distance between the ultra-high frequency acoustic resonator provided at the bottom of the reservoir and the patient's skin.
  • the area of the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator in the device is about 1,000-50000 ⁇ m 2 , preferably about 5000-20000 ⁇ m 2 .
  • the power of the bulk acoustic wave generated by the UHF acoustic wave resonator in the device is about 0.1-50W, preferably 0.2-10W, more preferably 0.5-5W.
  • transdermal drug delivery composition which comprises:
  • One or more ultra-high frequency bulk acoustic wave resonators detachably arranged at the bottom of the storage, and the one or more ultra-high frequency bulk acoustic wave resonators generate a frequency of about 0.5 in the solution or suspension -50GHz bulk acoustic wave.
  • the solution or suspension or gel containing the active agent is in contact with 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 resonator is arranged such that the propagation direction of the bulk acoustic wave generated in the solution or suspension is toward the top of the reservoir, that is, the surface in contact with the patient's skin.
  • the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot diffuse freely.
  • the outer surface of the semipermeable membrane may also have a peelable closure membrane, which can be peeled off before use (in contact with the patient's skin).
  • the reservoir has an opening or an opening, which is suitable for adding a solution or a suspension, or a packaging bag containing a solution or a suspension or a gel.
  • the ultra-high frequency resonator in the composition has a circuit for receiving pulsed voltage signals.
  • the ultra-high frequency resonator has a circuit and an interface for receiving connection with an external high-frequency signal generator, and the interface is provided on the device housing.
  • the UHF resonator has a circuit that receives radio frequency signals.
  • the device further includes a timed emission signal system to excite the UHF bulk acoustic wave resonator within a specified time or time period.
  • the height of the reservoir (the distance from the bottom to the top, such as the semipermeable membrane to the top) of the composition is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1 -10mm.
  • the upper surface of the reservoir is in contact with the patient's skin, so the height of the reservoir is equivalent to the distance between the ultra-high frequency acoustic resonator provided at the bottom of the reservoir and the patient's skin.
  • transdermal drug formulation which includes:
  • a gel containing an active agent is usually in contact with the patient's skin on its top, that is, its upper surface;
  • One or more ultra-high frequency bulk acoustic wave resonators that are detachable in contact with the bottom of the gel, and the one or more ultra-high frequency bulk acoustic wave resonators are set to generate a frequency of about 0.5-50 GHz in the gel Body sound waves.
  • the propagation direction of the bulk acoustic wave generated in the gel by the UHF bulk acoustic wave resonator is toward the top of the gel, that is, the surface in contact with the patient's skin.
  • the gel is a hydrogel, especially a water-based hydrogel.
  • the upper surface of the gel has a semipermeable membrane through which the active agent cannot diffuse freely.
  • the upper surface of the gel has a skin adhesion layer,
  • the UHF resonator in the pharmaceutical preparation has a circuit for receiving pulse voltage signals.
  • the ultra-high frequency resonator has a circuit and an interface for receiving connection with an external high-frequency signal generator, and the interface is provided on the device housing.
  • the UHF resonator has a circuit that receives radio frequency signals.
  • the device further includes a timed emission signal system to excite the UHF bulk acoustic wave resonator within a specified time or time period.
  • the biologically active agent in the pharmaceutical preparation is a small molecule compound, polypeptide, protein, oligonucleotide, nucleic acid, and polysaccharide.
  • the molecular weight of the bioactive agent in the pharmaceutical preparation is 200 to 1,000,000 Daltons.
  • the thickness of the gel is about 0.1-20 mm, preferably 0.5-15 mm, and most preferably about 1-10 mm.
  • the upper surface of the gel is in contact with the patient's skin, so the thickness of the gel is equivalent to the distance between the ultra-high frequency acoustic resonator provided at the bottom of the gel and the patient's skin.
  • Fig. 1 shows an exemplary experimental device setup diagram of the present invention.
  • Fig. 2 shows an exemplary ultra-high frequency acoustic resonator of the present invention.
  • Fig. 3 shows a schematic diagram of an exemplary embodiment of the transdermal administration composition of the present invention.
  • the transdermal pharmaceutical composition is particularly suitable for using a solution or suspension or gel as a medium.
  • Fig. 4 shows a schematic diagram of another exemplary embodiment of the transdermal drug delivery composition of the present invention, which is particularly suitable for using gel as a medium.
  • FIG. 1 Set up the experimental device as shown in Figure 1. Among them are two wells with adjustable height surrounded by polydimethylsiloxane (PDMS) material walls.
  • the well below is closed and connected with a circuit board with an ultra-high frequency acoustic resonator to form a liquid supply pool that can contain liquid or gel.
  • the volume of the liquid supply tank was adjusted to about 30 ⁇ L, and the height was about 1 mm.
  • the resonator can generate a bulk acoustic wave with a frequency of about 0.5-50 GHz that travels to the top in the liquid of the chamber.
  • the upper well and the liquid supply tank are separated by semipermeable membranes and/or animal skin samples.
  • the upper well can be filled with solutions such as PBS to receive the active substances permeated from the liquid supply tank, also called receiving Pool
  • Fig. 2 is a physical photo of an exemplary ultra-high frequency acoustic wave resonator in the method and device of the present invention, and the area for generating a bulk acoustic wave is about 15000-20000 ⁇ m 2 .
  • Figure 2A shows the ratio of UHF acoustic resonator devices to coins.
  • Fig. 2B shows the area and pattern of the bulk acoustic wave generated by the UHF acoustic wave resonator (the pattern illustrated in the figure is a pentagon).
  • Fig. 3 is a schematic diagram of a transdermal drug delivery composition provided by the present invention, which is suitable for a solution or suspension or gel as a medium.
  • the transdermal drug delivery composition includes a reservoir 10 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 devices arranged at the bottom of the reservoir
  • the bulk acoustic wave resonator 30, the one or more ultra-high frequency bulk acoustic wave resonators generate a bulk acoustic wave with a frequency of about 0.5-50 GHz in the solution or suspension.
  • the solution or suspension containing the active agent is brought into contact with 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 resonator is arranged such that the propagation direction of the bulk acoustic wave generated in the solution or suspension is toward the top of the reservoir, that is, the surface in contact with the patient's skin.
  • the upper surface of the reservoir has a semipermeable membrane 40 through which the active agent cannot diffuse freely.
  • Fig. 4 is a schematic diagram of another exemplary transdermal drug formulation provided by the present invention, which is suitable for using a gel as a medium.
  • the transdermal drug formulation includes a gel 110 containing an active agent; a plurality of ultra-high frequency bulk acoustic wave resonators 120 in contact with the bottom of the gel, and the one or more ultra-high frequency bulk acoustic wave resonators
  • the generator generates a bulk acoustic wave with a frequency of about 0.5-50 GHz in the gel.
  • the bottom layer of the gel has a support layer 140, and the UHF resonator is detachably assembled on the support layer.
  • the gel usually contacts the patient's skin with its top, that is, its upper surface.
  • the UHF bulk acoustic wave resonator is arranged such that the propagation direction of the bulk acoustic wave generated in the gel is toward the top of the gel, that is, the surface in contact with the patient's skin.
  • the upper surface of the gel has a semi-permeable membrane 130 through which the active agent cannot diffuse freely.
  • the outer surface of the semipermeable membrane may also have a peelable sealing membrane 150.
  • the UHF acoustic resonator 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 bulk acoustic wave generation area.
  • the top surface of the ultra-high frequency acoustic wave resonator is arranged at the bottom of the PDMS well, and a bulk acoustic wave is generated toward the top of the well; the area formed by the top surface may be called a bulk acoustic wave action area.
  • the bulk acoustic wave generation area of the ultra-high frequency acoustic wave resonator is about 15000-20000 ⁇ m 2 .
  • the main steps include:
  • the bulk acoustic wave resonator device was fabricated on a 100mm undeposited Si wafer, starting from the deposition of the Bragg reflector, which was made by AlN and SiO2 layers alternately deposited by PVD and CVD, respectively. Then layer by layer deposition and patterning includes a bottom electrode layer (BE), piezoelectric layer (AlN) and top electrode layer (TE) sandwich structure.
  • BE bottom electrode layer
  • AlN piezoelectric layer
  • TE top electrode layer
  • the bottom electrode layer (BE) is made of 600nm thick Mo and deposited on the top of the Bragg reflector by PVD, then the film is patterned by photolithography and plasma etching (for example, patterned into a pentagon or triangle), and then PVD A piezoelectric layer is deposited, which is an AlN film with a thickness of 1000 nm on top of the BE, with a crystal orientation along the c-axis.
  • the top electrode layer (TE) of gold deposited using electron beam evaporation and then wet etching covers the resonator, where the thickness of the Au electrode and the underlying Cr binder layer are about 300 nm and about 50 nm, respectively.
  • the electrode area is configured to 20,000 ⁇ m 2 so that the resonator has a characteristic impedance of 50T to match the impedance of the external circuit.
  • the walls of polydimethylsiloxane (PDMS) devices were prepared by soft lithography.
  • 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 adjusting device.
  • Fluorescence labeling method is used to determine the content. Take the commercially available fluorescently-labeled dextran (FITC-CM-Dextran, SIGMA) to make a 2mg/ml mother solution, and dilute it for 12 times in order of twice the amount to obtain 0.0005-2mg/ml standard solution. Fluorescence quantitative microplate reader (SpectraMax Gemini EM) was used to determine the concentration in sequence to establish a linear standard curve. Place the experimental sample in the well of the plate to be tested to read the fluorescence value, and refer to the concentration standard curve to determine the concentration of the sample to be tested.
  • FITC-CM-Dextran fluorescently-labeled dextran
  • SIGMA fluorescently-labeled dextran
  • CM-Dextran, SIGMA dextran
  • Table 1 The results of special sonic boosting 4000 molecular weight dextran through RC-1000 membrane
  • FITC-CM-Dextran fluorescently labeled dextran
  • SIGMA fluorescently labeled dextran
  • take 30ul into the liquid supply tank and use cellulose ester membrane EC-1000 membrane (MD31, Spectrumlabs capped the top and pressed the receiving tank tightly on the liquid supply tank, and injected 300ul PBS into the receiving tank.
  • the effect of dextran through the cellulose ester membrane was measured under the conditions of no power control and power, respectively. Sampling 50ul at 60, 90 minutes, the power condition is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Each group of experiments is repeated 3 times.
  • Insulin content determination method use octadecylsilane-bonded silica gel as filler (5-10 ⁇ m); use 0.2mol/L sulfate buffer solution (take 28.4g of anhydrous sodium sulfate, add water to dissolve, add 1.7ml of phosphoric acid, Adjust the pH value of ethanolamine to 2.3, add water to 1000ml)-acetonitrile (74:26) as the mobile phase; the column temperature is 40°C; the detection wavelength is 214nm.
  • Example 8 The effect of UHF body acoustic wave power change on insulin penetration through RC-1000 membrane
  • Example 7 The experiment was performed with the same experimental settings and parameters as in Example 7 to test the influence of the power of different activated UHF acoustic resonators.
  • the power is 500mW, 800mW, 1000mW, 2000mW. Each experiment was repeated 3 times. The results are shown in Table 7.
  • Table 7 The results of the effects of different power special sound waves on the RC-1000 membrane for promoting insulin penetration
  • Example 9 The effect of multi-chip combination on the penetration of insulin through RC-1000 membrane
  • Example 7 The experiment was performed with the same experimental settings and parameters as in Example 7, and the influence of using multiple ultra-high frequency acoustic resonators at the bottom of the same liquid supply tank was tested. 1, 2, 4 and 8 ultra-high frequency acoustic wave resonators are respectively arranged on the circuit board at the bottom of the liquid supply tank. Each experiment was repeated 3 times. The results are shown in Table 8.
  • FITC-CM-Dextran FITC-CM-Dextran
  • SIGMA fluorescently labeled dextran
  • the rat's isolated skin is capped, and the receiving tank is pressed against the supply tank with the SD rat's isolated skin tightly separated, and 300ul PBS is injected into the receiving tank.
  • the effects of dextran through rat skin were measured on the control and power-up conditions of activating the ultra-high-frequency acoustic wave resonator to generate bulk acoustic waves. 50ul samples were taken at 30, 60, and 90 minutes, and the power was added. It is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Each experiment was repeated 3 times.
  • the determination method of content and molecular weight is the same as in Example 2.
  • the results are shown in Table 9. The results indicate that the effect of special sonic waves can promote the penetration of dextran with a molecular weight of 4000 through rat skin.
  • Example 11 Promoting 40,000 molecular weight dextran to penetrate rat skin
  • the determination method of content and molecular weight is the same as in Example 2.
  • the results are shown in Table 10.
  • the results show that the effect of special sonic waves can promote the penetration of 40,000 molecular weight dextran through rat skin.
  • the determination method of content and molecular weight is the same as in Example 2.
  • the results are shown in Table 11.
  • the results show that the effect of special sonic waves can promote the penetration of 500,000 molecular weight dextran through rat skin.
  • Table 11 The results of special sonic wave promoting 500,000 molecular weight dextran through rat skin
  • the method for measuring insulin content is the same as in Example 7.
  • the results are shown in Table 12, indicating that the effect of special sonic waves can promote the penetration of insulin through rat skin.
  • Example 14 The effect of power changes on the penetration of insulin through rat skin
  • Example 13 Experiments were carried out with the same experimental settings and parameters as in Example 13, to test the influence of the power of different activated UHF acoustic resonators.
  • the power is 500mW, 800mW, 1000mW, 2000mW. Each experiment was repeated 3 times. The results are shown in Table 13.
  • Example 15 The effect of multi-chip combination on the penetration of insulin through rat skin
  • Example 14 The experiment was carried out with the same experimental settings and parameters as in Example 13, and the effect of using multiple UHF acoustic resonators at the bottom of the same liquid supply tank was tested. 1, 2, 4 and 8 ultra-high frequency acoustic wave resonators are respectively arranged on the circuit board at the bottom of the liquid supply tank. Each experiment was repeated 3 times. The results are shown in Table 14.
  • Example 16 Promoting 40,000 molecular weight dextran to penetrate rat skin through EC-1000 membrane
  • the effect of dextran through rat skin was measured on the control and power-on conditions where the ultra-high frequency acoustic resonator was activated without power to generate the bulk acoustic wave, and 50ul was sampled at 30, 60, and 90 minutes.
  • the power condition of the UHF sonic resonator is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Each experiment was repeated 3 times.
  • Example 17 Insulin permeates rat skin through semi-permeable membrane and the effect of special ultrasound frequency
  • STZ streptozotocin
  • the blood glucose changes were detected at 2, 4, 6, 8, 10, and 12 hours, and compared with the synchronized blood glucose of the normal anesthesia non-administered group, and an equal amount of intravenous insulin group was set up as a positive control. Each experiment was repeated 3 times. The results are shown in Table 17.
  • the power group can significantly reduce the blood glucose content in the animal, indicating that the transdermal effect is significant.
  • the enhanced power group has the effect of sustained drug release and can maintain a significant blood sugar lowering effect within 8 hours, while the intravenous injection group reaches the maximum hypoglycemic effect in 2 hours, the fourth It loses its effective blood sugar lowering effect after hours. It can be seen that the hypoglycemic effect of the special sonic wave promoting skin penetration method and device of the present invention has the characteristics of high efficiency and long effect, and has obvious advantages compared with the prior art.
  • Example 1 of Chinese invention patent CN108653198 an insulin hydrogel formulation without transdermal peptide was prepared.
  • the specific method is:
  • PEG-DA polyethylene glycol diacrylate
  • the white powder obtained is polyethylene glycol diacrylate.
  • the preparation method of hydrogel includes the following steps:
  • the tailored insulin hydrogel preparation is attached to the surface of the UHF bulk acoustic wave resonator, the release surface is attached to the RC-1000 membrane (JMD38, Solarbio), and the other side of the membrane is in close contact with the receiving pool. Inject 300ul of PBS into the pool.
  • the transdermal effect of insulin was measured under the conditions of no power to activate the ultra-high frequency acoustic resonator and power, respectively, as control and test samples.
  • the power condition is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Samples were taken at 30, 60, and 90 minutes to determine the transdermal efficiency of insulin. Each experiment was repeated 3 times. The results are shown in Table 3, indicating that the special sonic effect can significantly improve the membrane penetration of the insulin hydrogel preparation.
  • the insulin hydrogel preparation prepared in Example 19 was cut to a size corresponding to the UHF bulk acoustic wave resonator device.
  • the tailored insulin hydrogel preparation was attached to the surface of the UHF bulk acoustic wave resonator, the release surface was sealed with the rat abdomen skin, the other side of the rat skin was in close contact with the receiving pool, and 300ul PBS was injected into the collection pool.
  • the transdermal effects of insulin were measured under the conditions of no power and power, respectively, as control and test samples.
  • the power condition is 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Samples were taken at 30, 60, and 90 minutes to determine the transdermal efficiency of insulin. Each experiment was repeated 3 times.
  • the insulin content determination method is the same as in Example 2. The results are shown in Table 19, indicating that the special sonic effect can significantly improve the rat skin penetration effect of the insulin hydrogel formulation.
  • the insulin hydrogel preparation prepared in Example 19 was cut to a size corresponding to the UHF bulk acoustic wave resonator device.
  • the tailored insulin hydrogel preparation is attached to the surface of the ultra-high frequency bulk acoustic wave resonator to form an insulin drug hydrogel transdermal patch. It was attached to the abdomen of rats anesthetized with ether, and the transdermal effect of insulin was measured under the conditions of not adding power to activate the ultra-high frequency acoustic resonator to generate bulk acoustic waves and adding power, respectively, as control and test samples.
  • the power condition is 500mW, 2.58GHz, 0.5S pressure pulse, 0.5S interval.
  • the drug is released for 90 minutes.
  • the blood glucose changes were detected at 2, 4, 6, 8, 10, and 12 hours, and compared with the synchronized blood glucose of the normal anesthesia non-administered group, and an equal amount of intravenous insulin group was set up as a positive control. Each experiment was repeated 3 times. The results are shown in Table 20.
  • the power group can significantly reduce the blood glucose content in the animal body, indicating that the transdermal effect is significant; compared with the intravenous administration group, the power group has sustained drug release The effect is that it can maintain a significant blood sugar lowering effect within 10 hours, while the intravenous administration group reaches the maximum blood sugar lowering effect in 2 hours, and the effective blood sugar lowering effect is lost after the 4th hour. It can be seen that the hypoglycemic effect of the special sonic transdermal preparation of the present invention has the characteristics of high efficiency and long-term effect, and has obvious advantages compared with the prior art.
  • the detection method of flurbiprofen is as follows: take this product, accurately weigh it, add a solvent [acetonitrile-water (45:55)] to dissolve and dilute to make a solution containing about 2.0mg per 1ml as a reference solution, at different times Sampling is the test product.
  • a solvent acetonitrile-water (45:55)] to dissolve and dilute to make a solution containing about 2.0mg per 1ml as a reference solution, at different times Sampling is the test product.
  • Table 21 The results of special sonic wave promoting flurbiprofen hydrogel to penetrate RC-1000 membrane
  • the present invention provides a new method and device for transdermal administration of biologically active substances by using ultra-high frequency resonators to generate bulk acoustic waves, especially for drug molecules that are difficult or impermeable to the skin.
  • the inventor unexpectedly discovered that the UHF resonator generated bulk acoustic waves can effectively pass small molecule compounds and proteins through the semipermeable membrane, and even through the skin of the animal body, thereby providing safe and convenient delivery of small molecules.
  • Methods and devices for molecular chemical drugs, peptide drugs, and biological drugs such as antibodies and vaccines.
  • the inventors also solved a method for preparing active substances in liquids into drug delivery compositions and devices, including encapsulation by translucent films.

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Abstract

一种利用超高频谐振器产生体声波来促使药物透皮释放的方法和装置。方法能够实现不易或不可透皮物质的透皮，包括但不限于小分子化学药、多肽药物以及抗体及疫苗等生物活性物质。

Description

透皮给药方法、制剂和装置
本申请要求以下中国专利申请的优先权：2019年6月10日提交的、申请号为201910496314.8、发明名称为“透皮给药方法和装置”；2019年6月10日提交的、申请号为201910496333.0、发明名称为“透皮给药凝胶制剂和其应用”。其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物释放方法和装置。更具体的，本发明涉及利用超高频谐振器产生体声波来促使药物透皮释放的方法和装置。本发明的方法能够实现不易或不可透皮物质的透皮，包括但不限于小分子化学药、多肽药物以及抗体及疫苗等生物活性物质。
背景技术
皮肤披覆在人体的表层，防止外界物质进入人体，具有重要的保护功能。皮肤由表皮和真皮紧密结合而成。其中表皮由复层扁平上皮构成，由浅入深依次为角质层，透明层、颗粒层和生发层。角质层由多层角化上皮细胞构成，无生命，不透水，是外源性物质透过皮肤吸收的主要屏障。真皮由致密结缔组织构成，其内有丰富的胶原纤维，弹力纤维和网状纤维，它们互相交织成网，使皮肤具有较大弹性和韧性。
本文中使用的通用术语“透皮”是指使活性剂(例如治疗剂例如药物，或免疫活性剂例如疫苗)穿过皮肤释放至局部组织或全身循环系统，基本上不需要切割或刺穿皮肤，例如用手术刀切割或用皮下针刺入皮肤。透皮给药系统优点体现在：药物吸收不受消化道内pH、食物、转运时间等因素影响；避免肝脏首过效应；克服因吸收过快产生血药浓度过高而引起的不良反应；可持续控制给药速度，灵活给药等。
皮肤给药系统中，表皮尤其是角质层是药物进入体内的主要屏障，研究发现只有极少数药物具有优良的皮肤透过性，多数药物不易穿过人体皮 肤这一有效的，选择性的屏障。
目前动态打开角质层致密结构实现促透皮给药的技术主要有化学促透、物理促透(电导、微针)等。化学促透主要通过是一种能可逆改变皮肤角质层屏障功能而又不损伤任何活性细胞、增强药物透皮能力、提高药物透皮量的物质来实现。化学促透的优势是可与药物制剂整合在一起，但用量较大或时间较长时会产生皮肤红肿、疼痛等刺激，与药物成分的相容性也是制约其应用的重要因素。
常用的单一物理技术促渗方法有微针、驻极体、离子、电致孔、激光、磁场导入、热穿孔。微针促渗是将由数十至数百枚空心或实心显微针组成的透皮贴片贴于皮肤，穿透角质层屏障并在表皮层制造出微小通道，药物通过微小通道进入体循环，可促进药物经皮渗透到特定的部位，适用于大分子药物(如皮肤渗透率较低的多肽、蛋白质和疫苗等)。电致孔技术是指在瞬间高电压脉冲电流作用下，脂质双分子层的无序结构增加形成短暂、可逆的亲水性孔道，从而提高细胞及组织膜渗透性，但依赖带电装置及能量的特点导致推广受限。激光技术是利用激光冲击靶物质形成的光机械波对皮肤造成的冲击，促进大分子药物透皮吸收的一种物理促渗技术。磁场导入促渗是一种应用磁场提高药物经皮渗透率的物理技术。热穿孔技术是采用脉冲加热法在角质层中形成亲水性通道以增加皮肤渗透性的一种技术。磁场导入与热穿孔技术制作的复杂性和高成本是亟需突破的难题。
已报道采用超声导入药物的方法，其具体的作用机制至今仍末完全阐明，目前主流的观点认为空化作用是超声促透的最主要作用机制。空化作用是指超声波在介质的传播中，气体空泡形成、扩张、收缩以及崩解的过程。现有的研究结果表明频率越低空化效果越好，因此使用低频率(尤其是20KHz)的超声和使用一些表面活性物质来降低液体介质表面的张力是提高空化效果提高药物渗透率研究的主要方向。
本领域还需要有效和安全的透皮给药方法和装置。
发明内容
本发明提供了新的利用超高频谐振器产生体声波来实现生物活性物质的透皮，特别是对不易或不可透皮药物分子的透皮给药方法和装置。本发明提供的方法可以有效和安全地递送小分子化学药、多肽药物以及抗体及疫苗等生物药。
具体的，本发明提供了将生物活性剂通过透皮释放给予患者的方法，所述方法包括：
(1)提供含有生物活性剂的储库(reservoir)，所述储库用于容纳含有活性剂的溶液、悬浮液或凝胶，
(2)激活一个或多个超高频声波谐振器，在所述溶液、悬浮液或凝胶中产生频率为约0.5-50GHz的体声波，使得所述生物活性剂进入或透过患者的皮肤。
本文中所使用术语“透皮”指为局部或全身治疗目的，使得药物进入和/或通过皮肤而达到释放。
患者是指人或其它动物，包括而不限于其他灵长类如黑猩猩和其他无尾猿及猴类；农场饲养动物如牛、羊、猪、山羊和马；家养动物如狗和猫；实验室动物包括啮齿类如小鼠、大鼠和天竺鼠；鸟类，包括家养的、野生的和玩耍鸟类如小鸡、火鸡和其它鸡形目鸟、鸭、鹅等。
生物活性剂指含有活性剂或药物的物质或混合物的组合物，其在以治疗有效量给予患者时药理上有效。生物活性剂的实例包括但不限于小分子量化合物、多肽、蛋白质、寡核苷酸、核酸和多糖。
在本发明的方法中，所述生物活性剂的分子量的范围为200～1000000道尔顿。
在本发明的方法中，所述生物活性剂也可以通过附着在载体上进行递送。载体可以是用在生物技术中用于固定的任何固体基质。具体载体包括硅石、玻璃、无机载体例如金属纳米颗粒或氧化铝、有机载体例如聚合物载体(例如聚苯乙烯)。优选地，固体载体是聚合物颗粒，特别是聚合物微粒，直径可为50nm到500μm，例如100nm到100μm。
“生物活性剂”的实例包括但不限于促黄体生成激素释放激素(LHRH)；LHRH类似物(例如戈舍瑞林、亮丙立德、布舍瑞林、曲普瑞林、 戈那瑞林和napfarelin、尿促性素(尿促滤泡素(FSH)和LH))；加压素；去氨加压素；促肾上腺皮质激素(ACTH)；ACTH类似物例如ACTH(1-24)；降钙素；加压素；脱氨基[Val4、D-Arg8]精氨酸加压素；α干扰素；β干扰素；γ干扰素；红细胞生成素(EPO)；粒细胞巨噬细胞集落刺激因子(GM-CSF)；粒细胞集落刺激因子(G-CSF)；白介素-10(IL-10)；胰高血糖素；生长素释放因子(GHRF)；胰岛素；促胰岛素；降钙素；奥曲肽；内啡肽；TRN；NT-36(化学名称：N-[[(S)-4-氧代-2-氮杂环丁烷基]羰基]-L-组氨酰基-L-脯氨酰胺)；liprecin；αANF；βMSH；促生长素抑制素；缓激肽；生长激素；血小板衍生生长因子释放因子；木瓜凝乳蛋白酶；缩胆囊素；绒膜促性腺激素；依前列醇(血小板凝集抑制剂)；胰高血糖素；比伐卢定；干扰素；白介素；尿促性素(尿促滤泡素(FSH)和LH)；催产素；链激酶；组织纤溶酶原激活物；尿激酶；ANP；ANP清除抑制剂；BNP；VEGF；血管紧张素II拮抗剂；抗利尿素激动剂；缓激肽拮抗剂；ceredase；CSI’s；降钙素基因相关肽(CGRP)；脑啡肽；FAB片段；IgE肽抑制因子；IGF-1；神经营养因子；集落刺激因子；甲状旁腺激素和激动剂；甲状旁腺激素拮抗剂；前列腺素拮抗剂；喷替吉肽；蛋白C；蛋白S；肾素抑制剂；胸腺素α-1；溶栓药；TNF；加压素拮抗剂类似物；α-1抗胰蛋白酶(重组体)；TGF-β；磺达肝素；阿地肝素；达肝素；去纤苷；依诺肝素；水蛭素；那屈肝素；瑞肝素；亭扎肝素；戊聚糖多硫酸酯；寡核苷酸和寡核苷酸衍生物例如formivirsen；阿仑膦酸；氯膦酸；依替膦酸；伊班膦酸；英卡膦酸；帕米膦酸；利塞膦酸；替鲁膦酸；唑来膦酸；阿加曲班；RWJ445167；RWJ-671818；芬太尼；瑞芬太尼；舒芬太尼；阿芬太尼；洛芬太尼；卡芬太尼及其混合物。
本发明的方法特别适合用于不易或不可透皮的药物活性剂。例如，体积较大的活性剂如多肽或蛋白质。其中，蛋白质可包括细胞因子、激素、维生素、表面受体、半抗原、抗原、抗体、酶、生长因子、重组蛋白质、毒素、以及其片段和组合。另外，本领域存在各种因疏水性等物理性质不适合或无法通过常用的透皮制剂的小分子药物。
在本发明的方法中，所述活性剂存在溶液或悬浮液或凝胶中。在本 发明的其中又一个方面，所述溶液或悬浮液或凝胶与患者皮肤接触。在本发明的其中另一个方面，所述溶液或悬浮液或凝胶通过半透膜与患者皮肤接触。所述溶液或悬浮液或凝胶可直接加入到本发明装置的储库内，以半透膜封包储库的上表面。所述溶液或悬浮液或凝胶也可以以预封装的形式被提供。封装的材料包括半透膜。
在本发明的方法中，所述溶液或悬浮液或凝胶中为各种所述生物活性剂可溶的溶剂。在本发明的其中一个方面，所述溶液或悬浮液或凝胶所含的溶剂为水性溶剂，例如水。在本发明的其中另一个方面，所述溶液也可包括非水溶剂例如乙醇、氯仿、醚、丙二醇、聚乙二醇等。在本发明的方法中，除了生物活性剂，所述溶液、悬浮液或凝胶中还可含有惰性填充剂；渗透促进剂；赋形剂及其他药品或本领域已知的透皮装置的常规组分。
可用于本发明的方法的凝胶可以是各种天然或聚合物凝胶，例如为水凝胶(hydrogel)。水凝胶可以是天然存在的(如琼脂糖、葡聚糖、壳多糖、基于纤维素的化合物、淀粉、衍生淀粉等)或是合成制备的或者是改性的(如聚乙二醇PEG)。水凝胶是含有大分子三维网络，使得它在有水存在时膨胀、缺水时(或通过减少水量)皱缩但不溶于水的物质。相邻大分子之间的交联导致水凝胶的水不溶性。虽然有时在聚合物工业中把适用于本发明的大分子材料的干燥状态称作“干凝胶”而水合态称作“水凝胶”，但是为了本专利申请的目的，术语“水凝胶”是指无论无水还是水合的大分子材料。水凝胶最具特性之处在于无论是在脱水还是水合状态下材料保持常规形状。因此，如果水凝胶在脱水状态时大致呈球形，那么在水合状态时将呈球形。
本发明采用的水凝胶优选为基于水(water-based)的水凝胶，因为其具有较高的水含量和生物相容性。本发明采用的水凝胶中的聚合物包括但不限于羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、甲基纤维素(MC)、羟乙基甲基纤维素(HEMC)、乙基羟乙基纤维素(EHEC)、羧甲基纤维素(CMC)、聚(乙烯醇)、聚(环氧乙烷)、聚(2-羟乙基甲基丙烯酸酯)、聚(正-乙烯基吡咯烷酮)及泊洛沙姆。优选的聚合物材料为纤维素衍生物。
活性剂可以这样与水凝胶结合的：活性剂水性扩散进入大分子网络中，然后干燥大分子材料，从而将活性剂固定于水凝胶中。活性剂与水凝胶的结合可以是均匀分散并彻底吸收在产生的水凝胶中，或者是部分分散于仅一部分水凝胶颗粒中。其它方式或者可供选用的方式是，活性剂与水凝胶的结合是由于在两个成份之间形成离子或共价键，活性剂主要地包含在水凝胶基质中或者与水凝胶结构的表面结合(如键合)。水凝胶一旦遇含水环境，那么大分子网络将会膨胀，由此而释放出活性剂，活性剂。
在本发明的方法中，所述半透膜为所述活性剂不能自由扩散通过的半透膜。可用于本发明的方法的半透膜指业内公知的各种对不同分子量大小化合物具有选择性阻留的天然和人工膜，包括但不限于胶棉半透膜、羊皮纸半透膜、聚合物半透膜如纤维素酯膜、再生纤维素膜、聚丙烯膜等。
在本发明的方法中，生物活性剂可以以任何可能的含量存在在所述溶液、悬浮液或凝胶中。合适的含量可以参照本领域已知的透皮制剂，也可以通过已知的方法进行测试得知。例如，由于本发明的方法可以通过控制超高频声波谐振器发生声波的各种参数调整透皮的活性剂的量，因此可以通过实验检测和选择合适的在溶液、悬浮液或凝胶中的含量，以确保实施活性剂以治疗有效量和安全的量给予患者。
在本发明的方法中，采用含有生物活性剂的储库(reservoir)。所述储库适于容纳溶液、悬浮液或凝胶。所述活性剂的溶液或悬浮液可直接加入到所述储库内，然后以半透膜封包储库的上表面，也可以以预封装的形式被提供。封装的材料可以为半透膜等。例如，所述储库具有四个边框，用于容纳溶液或悬浮液或凝胶。又例如，所述储库具有二-四个边框或卡槽，用于容纳溶液或悬浮液的封装袋，或用于容纳凝胶片或凝胶块。在本发明的其中一个方面，储库就是所述凝胶，如凝胶片和凝胶块。
在本发明的方法中，利用超高频声波谐振器在溶液中产生超高频(约0.5-50GHz)体声波。超高频形成的体声波区域中的粒子(如生物活性剂)受到流体拖拽力(Stokes drag force)，层流产生的惯性拖拽力(inertial lift force)和声波衰减引起的声辐射力(acoustic radiation force)的共同作用。在合适的条件下(溶液和粒子的性质、体声波的强度、粒子移动的距 离等)，体声波引发溶液中的粒子在沿声波传播方向的流动，能够穿过皮肤进入到皮肤内部，并且不引起皮肤的不可逆的损伤。
本发明采用的超高频声波谐振器可产生超高频(约0.5-50GHz)的振动，在溶液中引发相应频率的体声波。在本发明的其中一个方面，所述超高频声波谐振器为薄膜体声波谐振器(FBAR)或固态装配型谐振器(SMR)，优选为固态装配型谐振器。在本发明的其中又一个方面，所述超高频声波谐振器为厚度伸缩振动模式的声波谐振器，压电材料薄膜层在垂直方向上生长而制成，通过d33压电系数耦合垂直电场激发振动。本发明采用的超高频声波谐振器可以在装置和液体的界面产生局部化的声流，不需要耦合介质或结构的帮助。本发明的声波谐振器包括由下往上依次设置的声波反射层、底电极层、压电层及顶电极层。所述底电极层、压电层、顶电极层及声波反射层相重叠区域构成体声波产生区域。所述超高频声波谐振器的顶部表面配置在容纳液体的容器的壁(例如本发明的储库的底部)上，向对侧的壁产生传播方向与所述壁垂直的体声波；由所述顶部表面构成的区域可称为体声波作用区域。本发明的超高频声波谐振器的压电层的厚度范围为约1nm～2um。本发明的超高频声波谐振器的频率在约0.5-50GHz，优选为约1-10GHz。
在本发明中，所述声波作用区域的形状可以为任意形状。在本发明的其中一个方面，所述超高频声波谐振器的体声波产生区域宽度为约50-300μm，例如为约70-150μm。在本发明的其中又一个方面，所述超高频声波谐振器的体声波产生区域面积为约1000-50000μm 2，优选为约5000-20000μm 2。
在本发明的其中一个方面，在所述将生物活性剂通过透皮释放给予患者的方法中，所述超高频声波谐振器与患者的皮肤的距离为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。
本申请的发明人出乎意料地发现，在超高频声波谐振器与患者的皮肤的距离为约0.1-20mm时，能够有效地使活性剂透过皮肤，同时能够保持蛋白质等生物分子的活性，而且透皮效率较高。在本发明的其中又一个方面，所述储库的高度为约0.1-20mm，优选为0.5-15mm，最优选是约 1-10mm。在给药时，所述储库的上表面与患者的皮肤接触，因此所述储库的高度相当于所述超高频声波谐振器与患者的皮肤的距离。
在本发明的其中一个方面，可以通过体声波的功率来调节生物活性剂透皮的效率。所述微流控设备通过功率调节装置调节所述超高频声波谐振器产生的体声波的功率。所述功率调节装置的输出功率为约0.1-50W，优选为0.2-10W，更优选为0.5-5W。
所述超高频声波谐振器产生的体声波由高频信号发生器的信号驱动。驱动谐振器的脉冲电压信号可以用脉冲宽度调制驱动，脉冲宽度调制可以产生任何期望的波形，例如正弦波、方波、锯齿波或三角波。脉冲电压信号也可以具有调幅或调频开始/停止能力，以开始或消除体声波。
在本发明的一个方面，还提供了将活性剂通过透皮释放给予患者的装置。所述装置包括：
容纳活性剂的储库；所述储库用于容纳含有活性剂的溶液或悬浮液或凝胶；在其中一个实施方式中，所述储库即为凝胶本身；
设置在所述储库的底部的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器在所述溶液或悬浮液中产生频率为约0.5-50GHz的体声波。含有活性剂的溶液或悬浮液通过所述储库的顶部和患者皮肤接触。所述一个或多个超高频体声波谐振器设置在储库底部。超高频体声波谐振器设置为在所述溶液或悬浮液内产生的体声波的传播方向向着储库的顶部，即与患者皮肤接触的表面。
在本发明的其中一个方面，所述储库的上表面具有所述活性剂不能自由扩散通过的半透膜。在本发明的其中一个方面，所述半透膜的外表面还可具有可剥离的封闭膜，在使用(与患者皮肤接触)前剥离。
在本发明的一个方面，所述装置包括含有活性剂的凝胶；所述凝胶通常以其顶部，即其上表面与患者皮肤接触；
与所述凝胶的底部接触的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器设置在凝胶中产生频率为约0.5-50GHz的体声波。超高频体声波谐振器在所述凝胶中产生的体声波的传播方向向着凝胶的顶部，即与患者皮肤接触的表面。在本发明的其中一个方面，所述凝胶 为水凝胶(hydrogel)，特别是基于水(water-based)的水凝胶。在本发明的其中一个方面，所述凝胶的上表面具有活性剂不能自由扩散通过的半透膜。在本发明的其中一个方面，所述半透膜的外表面还可具有可剥离的封闭膜，在使用(与患者皮肤接触)前剥离。在本发明的其中一个方面，所述凝胶的上表面还具有皮肤粘附层，其可包含选自以下的聚合物膜：聚丙烯酸、壳聚糖、果胶、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟乙基纤维素(HEC)、或其它皮肤粘附性聚合物。在本发明的其中又一个方面，所述凝胶本身含有皮肤粘附性聚合物。
在本发明的其中一个方面，所述储库具有开口或开孔，适于加入溶液或悬浮液或凝胶，或装载容纳溶液或悬浮液或凝胶的封装袋，或用于装载凝胶(凝胶块或凝胶片等)。
在本发明的其中一个方面，所述装置还包括外壳，所述储库可装卸地与外壳连接。所述外壳具有适于与人体或动物体固定，使得所述储库的上表面保持与皮肤贴合的机构，例如扣带等。
在本发明的其中一个方面，所述装置中的超高频谐振器具有接收脉冲电压信号的电路。例如，所述超高频谐振器具有接受与外部高频信号发生器连接的电路和接口，所述接口设置在装置外壳上。又例如，所述超高频谐振器具有接受射频信号的电路。当所述活性剂需要长期给药或定时给药时，所述装置还包括定时发射信号系统，在指定的时间或时间段内激发超高频体声波谐振器。
在本发明的其中一个方面，所述储库的高度(底部到顶部，如到顶部的半透膜的距离)为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。在给药时，所述储库的上表面与患者的皮肤接触，因此所述储库的高度相当于设置在储库底部的超高频声波谐振器与患者的皮肤的距离。
在本发明的其中一个方面，所述装置中的超高频声波谐振器的体声波产生区域面积为约1000-50000μm 2，优选为约5000-20000μm 2。
在本发明的其中一个方面，所述装置中的超高频声波谐振器产生的体声波的功率为约0.1-50W，优选为0.2-10W，更优选为0.5-5W。
在本发明的一个方面，还提供了一种透皮给药组合物，其包括：
容纳含有活性剂的溶液或悬浮液或凝胶的储库；
可装卸地设置在所述储库的底部的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器在所述溶液或悬浮液中产生频率为约0.5-50GHz的体声波。含有活性剂的溶液或悬浮液或凝胶通过所述储库的顶部和患者皮肤接触。所述一个或多个超高频体声波谐振器设置在储库底部。超高频体声波谐振器设置为在所述溶液或悬浮液内产生的体声波的传播方向向着储库的顶部，即与患者皮肤接触的表面。
在本发明的其中一个方面，所述储库的上表面具有所述活性剂不能自由扩散通过的半透膜。在本发明的其中一个方面，所述半透膜的外表面还可具有可剥离的封闭膜，在使用(与患者皮肤接触)前剥离。
在本发明的其中一个方面，所述储库具有开口或开孔，适于加入溶液或悬浮液，或装载容纳溶液或悬浮液或凝胶的封装袋。
在本发明的其中一个方面，所述组合物中的超高频谐振器具有接收脉冲电压信号的电路。例如，所述超高频谐振器具有接受与外部高频信号发生器连接的电路和接口，所述接口设置在装置外壳上。又例如，所述超高频谐振器具有接受射频信号的电路。当所述活性剂需要长期给药或定时给药时，所述装置还包括定时发射信号系统，在指定的时间或时间段内激发超高频体声波谐振器。
在本发明的其中一个方面，所述组合物中的储库的高度(底部到顶部，如到顶部的半透膜的距离)为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。在给药时，所述储库的上表面与患者的皮肤接触，因此所述储库的高度相当于设置在储库底部的超高频声波谐振器与患者的皮肤的距离。
在本发明的一个方面，还提供了一种透皮释放的药物制剂，其包括：
含有活性剂的凝胶；所述凝胶通常以其顶部，即其上表面与患者皮肤接触；
与所述凝胶的底部接触的可装卸的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器设置为在凝胶中产生频率为约0.5-50GHz的体声波。超高频体声波谐振器在所述凝胶中产生的体声波的 传播方向向着凝胶的顶部，即与患者皮肤接触的表面。
在本发明的其中一个发明，所述凝胶为水凝胶(hydrogel)，特别是基于水(water-based)的水凝胶。在本发明的其中一个方面，所述凝胶的上表面具有活性剂不能自由扩散通过的半透膜。在本发明的其中一个方面，所述凝胶的上表面具有皮肤粘附层，
在本发明的其中一个方面，所述药物制剂中的超高频谐振器具有接收脉冲电压信号的电路。例如，所述超高频谐振器具有接受与外部高频信号发生器连接的电路和接口，所述接口设置在装置外壳上。又例如，所述超高频谐振器具有接受射频信号的电路。当所述活性剂需要长期给药或定时给药时，所述装置还包括定时发射信号系统，在指定的时间或时间段内激发超高频体声波谐振器。
在本发明的其中一个方面，所述药物制剂中的生物活性剂为小分子化合物、多肽、蛋白质、寡核苷酸、核酸和多糖。在本发明的其中一个方面，所述药物制剂中的生物活性剂的分子量为200～1000000道尔顿。
在本发明的其中一个方面，所述凝胶的厚度为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。在给药时，所述凝胶的上表面与患者的皮肤接触，因此所述凝胶的厚度相当于设置在凝胶底部的超高频声波谐振器与患者的皮肤的距离。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1示出本发明的一种示例性的实验设备设置图。
图2示出本发明的一种示例性的超高频声波谐振器。
图3示出本发明的透皮给药组合物的一种示例性实施方式的示意图。该透皮药物组合物特别适合以溶液或悬浮液或凝胶为介质。
图4示出本发明的透皮给药组合物的另一种示例性实施方式的示意图，该透皮药物组合物特别适合以凝胶为介质。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的区间。
实施例1 实验装置和材料制备
按图1所示设置实验装置。其中包括聚二甲基硅氧烷(PDMS)材料壁围成的上下两个高度可调的井。处于下方的井与具有超高频声波谐振器的电路板封闭连接，构成可容纳液体或凝胶的供液池。在实验中，调节供液池容积为约30μL，高度为约1mm。在供液池顶部用半透膜和/或鼠皮封盖。在供液池中加入含有活性物质的溶液或凝胶。谐振器可在腔室的液体中产生传向顶部的频率为约0.5-50GHz的体声波。上方的井与供液池之间根据不同实验，分别以半透膜和/动物皮肤样品相隔，上方的井可加入PBS等溶液，用于接收从供液池透过的活性物质，也称为接收池。
图2是本发明的方法和装置中一种示例性的超高频声波谐振器的实物照片，其产生体声波的面积约为15000-20000μm 2。图2A显示超高频声波谐振器器件与硬币的比例。图2B显示超高频声波谐振器产生体声波的面积和图案(在图中示例的图案为五角形)。
图3是本发明提供的一种透皮给药组合物的示意图，其适合以溶液或悬浮液或凝胶为介质。
其中，所述透皮给药组合物包括容纳活性剂的储库10；所述储库用于容纳含有活性剂的溶液或悬浮液20；设置在所述储库的底部的多个超高频体声波谐振器30，所述一个或多个超高频体声波谐振器在所述溶液或悬浮液中产生频率为约0.5-50GHz的体声波。含有活性剂的溶液或悬浮液通过 所述储库的顶部和患者皮肤接触。所述一个或多个超高频体声波谐振器设置在储库底部。超高频体声波谐振器设置为在所述溶液或悬浮液内产生的体声波的传播方向向着储库的顶部，即与患者皮肤接触的表面。所述储库的上表面具有所述活性剂不能自由扩散通过的半透膜40。
图4是本发明提供的另一种示例性的透皮释放的药物制剂的示意图，其适合以凝胶为介质。
其中所述透皮释放的药物制剂包括含有活性剂的凝胶110；与所述凝胶的底部接触的多个超高频体声波谐振器120，所述一个或多个超高频体声波谐振器在所述凝胶产生频率为约0.5-50GHz的体声波。所述凝胶的底层具有支持层140，所述超高频谐振器可装卸地装配在所述支持层。凝胶通常以其顶部，即其上表面与患者皮肤接触。超高频体声波谐振器设置为在所述凝胶内产生的体声波的传播方向向着凝胶的顶部，即与患者皮肤接触的表面。所述凝胶的上表面具有所述活性剂不能自由扩散通过的半透膜130。所述半透膜的外表面还可具有可剥离的封闭膜150。
超高频声波谐振器制备：
根据已报道的方法(Zhixin Zhang等，Small 2017，13，1602962-1602980)制备超高频声波谐振器。所述超高频声波谐振器包括由下往上依次设置的声波反射层、底电极层、压电层及顶电极层。所述底电极层、压电层、顶电极层及声波反射层相重叠区域构成体声波产生区域。所述超高频声波谐振器的顶部表面配置在所述PDMS井的底部，向所述井的顶部产生体声波；由所述顶部表面构成的区域可称为体声波作用区域。所述超高频声波谐振器的体声波产生区域面积为约15000-20000μm 2。
其主要步骤包括：
体声波谐振器装置在100mm未沉积Si晶片上制造，从沉积布拉格反射器开始，其分别通过PVD和CVD交替沉积的AlN和SiO2层制成。然后逐层沉积和图案化包括底电极层(BE)，压电层(AlN)和顶电极层(TE)的夹层结构。其中底电极层(BE)由600nm厚的Mo制成并通过PVD沉积在布拉格反射器的顶部上，然后通过光刻和等离子体蚀刻将膜图案化(例如图案化成五角形或三角形)，然后再PVD沉积压电层，压电层是 在BE的顶部上具有1000nm厚的AlN膜，具有沿c轴的晶体取向。在最后的步骤中，使用电子束蒸发然后湿蚀刻沉积的金的顶电极层(TE)覆盖谐振器，其中Au电极和下面的Cr粘合剂层的厚度分别为约300nm和约50nm。电极面积被配置为20,000μm 2，使得谐振器具有50T的特征阻抗，以匹配外部电路的阻抗。通过软光刻制备聚二甲基硅氧烷(PDMS)器件壁。
通过信号发生器和功率调节装置调节所述超高频谐振器产生的体声波的功率和时间间隔。
离体鼠皮制备
取体重约200克健康SD大鼠，用戊巴比妥麻醉后，用小剪刀小心减去腹部毛发，用剃须刀刮净，并避免刮破皮肤，剥离腹部皮肤，将皮肤平铺在玻璃板上，角质层朝下，用生理盐水棉球擦除皮下脂肪层和结缔组织。用生理盐水冲洗干净，浸泡在生理盐水中，当天取当天用。
实施例2 促4000分子量葡聚糖透RC-1000膜
取分子量为4000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)在PBS(pH7.4，gibco，Thermo Fisher Scientific)配成2mg/ml的供试液，取30ul注入供液池，用RC-1000膜(JMD38，Solarbio)封顶，然后将接收池紧密隔着所述半透膜压在供液池上，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器产生体声波的对照和加功率的条件上测定葡聚糖的透再生纤维素膜的效果，分别于30、60、90分钟时取样50ul。超高频声波谐振器功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
荧光标记法测定含量。取市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的母液，按2倍量依次稀适12次，得0.0005-2mg/ml标准液。采用荧光定量酶标仪(SpectraMax Gemini EM)依次测定建立浓度线性标准曲线。将实验取样样品置于待测板孔中读取荧光值，并参考浓度标准曲线确定待测样品浓度。
分子量的测定方法。取1000、5000、15000、50000、200000、500000 等不同分子量市售的葡聚糖(CM-Dextran，SIGMA)配成2mg/ml的母液，依次注入以水∶甲醇＝98∶2为液动相，装有PL aquagel MIXED-D凝胶柱(Agilent ltd.)和示差折光检测器的的液相分析系统(A gilent 1260)，流速为1ml/mim。根据出峰时间与分子量的线性关系建立标准曲线。将实验取样样品注入液相分析系统，通过保留时间从标准曲线中确定样品的分子量。
结果如表1所示，表明超高频声波谐振器产生的体声波(下文将其简称为“特声波”)的作用可促进4000分子量的物质透过截留分子量大于1000的半透膜。
表1 特声波促4000分子量葡聚糖透RC-1000膜结果
Figure PCTCN2020095399-appb-000001
-表示因浓度过低而未检出。
实施例3 促40000分子量葡聚糖透RC-1000膜
取分子量为40000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液。采用与实施例2同样的实验设置和参数进行实验。结果如表2所示，表明特声波的作用可促进40000分子量的物质透过截留分子量大于1000的半透膜。
表2 特声波促40000分子量葡聚糖透RC-1000膜结果
Figure PCTCN2020095399-appb-000002
Figure PCTCN2020095399-appb-000003
-表示因浓度过低而未检出。
实施例4 促500000分子量葡聚糖透RC-1000膜
取分子量为500000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液。结果如表3所示，表明特声波的作用可促进500000分子量的物质透过截留分子量大于1000的半透膜。
表3 特声波促500000分子量葡聚糖透RC-1000膜结果
Figure PCTCN2020095399-appb-000004
-表示因浓度过低而未检出。
实施例5 促4000分子量葡聚糖透EC-1000膜
取分子量为4000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液，取30ul注入供液池，用纤维素酯膜EC-1000膜(MD31，Spectrumlabs封顶，并将接收池紧密压在供液池上，在接收池中注入PBS 300ul。分别在不加功率对照和加功率的条件上测定葡聚糖的透纤维素酯膜的效果，分别于30、60、90分钟时取样50ul，加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
结果如表4所示，表明特声波的作用可促进4000分子量的物质透过截留分子量大于1000的纤维素酯膜半透膜。
表4 特声波促4000分子量葡聚糖透EC-1000膜结果
Figure PCTCN2020095399-appb-000005
Figure PCTCN2020095399-appb-000006
-表示因浓度过低而未检出。
实施例6 促500000分子量葡聚糖透RC-1000膜
取分子量为500000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液。采用与实施例5同样的实验设置和参数进行实验。结果如表6所示，表明特声波的作用可促进500000分子量的物质透过截留分子量大于1000的纤维素酯膜半透膜。
表5特声波促500000分子量葡聚糖透EC-1000膜结果
Figure PCTCN2020095399-appb-000007
-表示因浓度过低而未检出。
实施例7 促胰岛素透RC-1000膜
取市售胰岛素注射液(300IU/3ml，诺和灵30R，丹麦诺和诺德)30ul注入与器件相连的供液池，用RC-1000膜(JMD38，Solarbio)封顶，并将接收池紧密隔着所述半透膜压在供液池上，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。依次于30、60、90分钟时取样50ul，加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
胰岛素含量测定方法：用十八烷基硅烷键合硅胶为填充剂(5～10μm)；以0.2mol/L硫酸盐缓冲液(取无水硫酸钠28.4g，加水溶解后，加磷酸1.7ml，乙醇胺调节pH值至2.3，加水至1000ml)-乙腈(74∶26)为流动相； 柱温为40℃；检测波长为214nm。取系统适用性溶液20μl(取胰岛素对照品，加0.01mol/L盐酸溶液溶解并稀释制成每1ml中约含40单位的溶液，放置至少24小时)，注入液相色谱仪，记录色谱图，胰岛素峰与A21脱氨胰岛素峰(与胰岛素峰的相对保留时间约为1.2)之间的分离度应不小于1.8，拖尾因子应不大于1.8。精密量取20μl注入液相色谱仪，记录色谱图；另取胰岛素对照品适量，同法测定。按外标法以胰岛素峰面积与A21脱氨胰岛素峰面积之和计算，即得含量。
结果如表6所示，表明特声波的作用可促进胰岛素透过截留分子量大于1000物质的再生纤维素膜半透膜。
表6 特声波促胰岛素透RC-1000膜结果
Figure PCTCN2020095399-appb-000008
实施例8 超高频体声波功率变化对胰岛素透RC-1000膜的影响
采用与实施例7同样的实验设置和参数进行实验，测试不同激活超高频声波谐振器的功率的影响。功率分别为500mW、800mW、1000mW、2000mW。每组实验重复3次。结果如表7所示。
表7 不同功率特声波对促胰岛素透RC-1000膜影响的结果
Figure PCTCN2020095399-appb-000009
Figure PCTCN2020095399-appb-000010
结果表明，在一定的范围内，随着功率增加，特声波的促透效果同步提高。
实施例9 多芯片组合对胰岛素透RC-1000膜的影响
采用与实施例7同样的实验设置和参数进行实验，测试在同一供液池底部采用多个超高频声波谐振器的影响。分别在供液池底部的电路板上设置1、2、4和8个超高频声波谐振器。每组实验重复3次。结果如表8所示。
表8 不同数量芯片组合特声波对促胰岛素透RC-1000膜影响的结果
Figure PCTCN2020095399-appb-000011
结果表明随着特声波纳微芯片量的增加，特声波的促透效果同步提 高。
实施例10 促4000分子量葡聚糖透大鼠皮
取分子量为4000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液，取30ul注入供液池，用根据实施例1记载的方法制备的SD大鼠离体皮肤封顶，并将接收池紧密隔着SD大鼠离体皮肤压在供液池上，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器产生体声波的对照和加功率的条件上测定葡聚糖的透大鼠皮肤的效果，分别于30、60、90分钟时取样50ul，加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
含量及分子量的测定方法同实施例2。结果如表9所示，结果表明特声波的作用可以促分子量4000的葡聚糖透过大鼠皮肤。
表9 特声波促4000分子量葡聚糖透SD大鼠皮肤的结果
Figure PCTCN2020095399-appb-000012
-表示因浓度过低而未检出。
实施例11 促40000分子量葡聚糖透大鼠皮
取分子量为40000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液。采用与实施例10同样的实验设置和参数进行实验。
含量及分子量的测定方法同实施例2。结果如表10所示，结果表明特声波的作用可以促分子量40000的葡聚糖透过大鼠皮肤。
表10 特声波促40000分子量葡聚糖透SD大鼠皮肤的结果
Figure PCTCN2020095399-appb-000013
Figure PCTCN2020095399-appb-000014
-表示因浓度过低而未检出。
实施例12 促500000分子量葡聚糖透大鼠皮
取分子量为500000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液。采用与实施例10同样的实验设置和参数进行实验。
含量及分子量的测定方法同实施例2。结果如表11所示。结果表明特声波的作用可以促分子量500000的葡聚糖透过大鼠皮肤。
表11 特声波促500000分子量葡聚糖透大鼠皮肤的结果
Figure PCTCN2020095399-appb-000015
-表示因浓度过低而未检出。
实施例13 促胰岛素透大鼠皮
取市售胰岛素注射液(300IU/3ml，诺和灵30R，丹麦诺和诺德)30ul注入与器件相连的供液池，用根据实施例1记载的方法制备的SD大鼠离体皮肤封顶，并将接收池紧密压在供液池上，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器产生体声波的对照和加功率的条件上测定葡聚糖的透大鼠皮肤的效果，分别于30、60、90分钟时取样50ul，加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
胰岛素含量测定方法同实施例7，结果如表12所示，表明特声波的作用可促进胰岛素透过大鼠皮肤。
表12 特声波促胰岛素透SD大鼠皮肤的结果
Figure PCTCN2020095399-appb-000016
Figure PCTCN2020095399-appb-000017
实施例14 功率变化对胰岛素透大鼠皮的影响
采用与实施例13同样的实验设置和参数进行实验，测试不同激活超高频声波谐振器的功率的影响。功率分别为500mW、800mW、1000mW、2000mW。每组实验重复3次。结果如表13所示。
表13 不同功率特声波对促胰岛素大鼠皮肤影响的结果
Figure PCTCN2020095399-appb-000018
结果表明在一定范围内，随着功率增加，特声波的促透效果同步提高。
实施例15 多芯片组合对胰岛素透大鼠皮的影响
采用与实施例13同样的实验设置和参数进行实验，测试在同一供液 池底部采用多个超高频声波谐振器的影响。分别在供液池底部的电路板上设置1、2、4和8个超高频声波谐振器。每组实验重复3次。结果如表14所示。
表14 不同数量芯片组合特声波对促胰岛素透大鼠皮肤影响的结果
Figure PCTCN2020095399-appb-000019
结果表明随着特声波纳微芯片量的增加，特声波的促透效果同步提高。
实施例16 促40000分子量葡聚糖通过EC-1000膜透大鼠皮
取分子量为40000的市售荧光标记葡聚糖(FITC-CM-Dextran，SIGMA)配成2mg/ml的供试液，取30ul注入供液池，用RC-1000膜(JMD38，Solarbio)封顶，再覆上根据实施例1记载的方法制备的SD大鼠离体皮肤，然后将接收池紧密隔着SD大鼠离体皮肤压在供液池上，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器产生体声波的对照和加功率的条件上测定葡聚糖的透大鼠皮肤的效果，分别于30、60、90分钟时取样50ul。超高频声波谐振器功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。
结果如表15所示，表明特声波的作用可促进40000分子量的物质通过截留分子量大于1000的半透膜后透过大鼠皮肤。
表15 特声波促40000分子量葡聚糖透RC-1000膜和大鼠皮结果
Figure PCTCN2020095399-appb-000020
-表示因浓度过低而未检出。
实施例17 胰岛素通过半透膜透大鼠皮和特超声频率的影响
取市售胰岛素注射液(300IU/3ml，诺和灵30R，丹麦诺和诺德)30ul注入与器件相连的供液池，用RC-1000膜(JMD38，Solarbio)封顶，再覆上根据实施例1记载的方法制备的SD大鼠离体皮肤，然后将接收池紧密隔着SD大鼠离体皮肤压在供液池上。分别在不加功率和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。依次于30、60、90分钟时取样50ul，加功率条件为500mW，频率1.31GHz、1.82GHz、2.58GHz，2.84GHz，3.54GHz，0.5S加压脉冲，0.5S间隔。每组实验重复3次。结果如表16所示。
表16 不同频率特声波对促胰岛素透大鼠皮肤影响的结果
Figure PCTCN2020095399-appb-000021
Figure PCTCN2020095399-appb-000022
实施例18 大鼠体内促胰岛素透皮药效评价
采用重约200g SD的雄性大鼠，自由饮水和采食，并且每天更换垫料。在实验开始之前，所有的大鼠进入研究条件下经过为期3天的适应性喂养后，进行标记和称重，并根据45mg/kg的药量计算出每只大鼠进行糖尿病造模所需的STZ(链脲菌素)剂量。将100mg STZ溶于柠檬酸缓冲液(pH＝4.0，过膜除菌)中，根据不同SD大鼠的体重尾静脉注射相对应剂量的STZ溶液。4天后，将所有大鼠静脉注射取血检测血糖，血糖平均在16.7mmol/L以上，说明糖尿病造模成功。
取市售胰岛素注射液(300IU/3ml，诺和灵30R，丹麦诺和诺德)300ul注入供液池，用RC-1000膜(JMD38，Solarbio)紧密密封，将供液池固定于用乙醚麻醉的大鼠腹部，供液池的RC-1000膜一面与腹部接触。分别在不加功率激活超高频声波谐振器产生体声波和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。加功率条件为500mW，2.58GHz，0.5S加压脉冲，0.5S间隔，释药90分钟。在2、4、6、8、10、12小时检测血糖的变化，与正常麻醉不给药组的同步血糖对比，另设等量静注的胰岛素组对阳性对照。每组实验重复3次。结果如表17所示。
表17 特声波促胰岛素透大鼠皮肤的在体实验结果
Figure PCTCN2020095399-appb-000023
Figure PCTCN2020095399-appb-000024
实验发现，相同条件下，与不加功率激活超高频声波谐振器对照组相比，加功率组可显著降低动物体内血糖含量，说明透皮效果显著。与静注给药组相比，加功率组具有持续释药的效果，在8小时内均能维持显著的降血糖效果，而静注给药组在2小时达到最大降糖效果后，第4小时后即失去有效的降血糖作用。可见，本本发明的特声波促透皮方法和装置的降糖效果具有高效和长效的特点，与现有技术相比优势明显。
实施例19 促胰岛素水凝胶的RC-1000膜透膜
参考中国发明专利CN108653198的实施例1公开的方法制备不含透皮肽的胰岛素水凝胶制剂。具体方法为：
1、精氨酸的不饱和聚酯酰胺(U-Arg-PEA)的合成，包括以下步骤：
(1)将富马酰氯和对硝基苯酚在含有三乙胺的丙酮中于0℃下搅拌2h，然后在室温下过夜，得到单体I，在乙酸乙酯中重结晶3次；
(2)将精氨酸和1，4-丁二醇混合后，加入含有对甲苯磺酸一水合物的甲苯中，加热至130℃，并搅拌回流24h，然后将产物在75℃下搅拌溶解在异丙醇中，再于4℃沉淀3次，得到单体II；
(3)将单体I和单体II加入二甲基亚砜中混合均匀后，逐滴加入三乙胺，直至单体完全溶解；在75℃下搅拌48h后，用乙酸乙酯进行沉淀，溶于甲醇后，再用乙酸乙酯重复沉淀3次进行纯化，重复两次后，真空干燥，得到棕黄色固体，即为精氨酸的不饱和聚酯酰胺(U-ArgPEA)。
2、聚乙二醇二丙烯酸酯(PEG-DA)的合成，包括以下步骤：
(1)将聚乙二醇粉末放入圆底烧瓶，连接装置，氮气置换空气，且冰浴；
(2)往圆底烧瓶中加入30mL二氯甲烷溶解聚乙二醇后，加入0.6mL三乙胺，再往恒压漏斗中加入20mL二氯甲烷和2mL丙烯酰氯，将两者混合后以每秒一滴的速度滴加入圆底烧瓶中，氮气保护下，室温搅拌24h；
(3)使用400mL冰乙醚进行沉淀，经抽滤后再真空干燥，得到的白色粉末，即为聚乙二醇二丙烯酸酯。
3、水凝胶的制备方法，包括以下步骤：
(1)将质量比为1∶1的精氨酸的不饱和聚酯酰胺和聚乙二醇二丙烯酸酯均匀分散到水中，使两者的质量百分比之和为15％，并且加入适量的胰岛素，使胰岛素光引发剂和水的质量百分比之和为85％；
(2)加入1％的光引发剂I2959，充分混匀后注入模具，经强度为100mW/cm 2紫外光照射100s，得到水凝胶(Gel2：PEG-DA/U-Arg-PEA/Insulin/TD-1)。
取制备的胰岛素水凝胶制剂，剪裁至与超高频体声波谐振器器件相应的尺寸。将剪裁好的胰岛素水凝胶制剂与超高频体声波谐振器的表面相贴，释药面与RC-1000膜(JMD38，Solarbio)相贴，膜的另一面与接收池紧密接触，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。分别于30、60、90分钟取样测定胰岛素的透皮效率。每组实验重复3次。结果如表3所示，表明特声波作用可显著提高胰岛素水凝胶制剂的透膜作用。
表18 特声波促胰岛素透RC-1000膜的结果
Figure PCTCN2020095399-appb-000025
Figure PCTCN2020095399-appb-000026
实施例20 促胰岛素水凝胶透大鼠皮
取实施例19制备的胰岛素水凝胶制剂，剪裁至与超高频体声波谐振器器件相应的尺寸。将剪裁好的胰岛素水凝胶制剂与超高频体声波谐振器的表面相贴，释药面与大鼠腹部皮肤密封，鼠皮另一面与接收池紧密接触，收集池注入300ul PBS。分别在不加功率和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。分别于30、60、90分钟取样测定胰岛素的透皮效率。每组实验重复3次。胰岛素含量测定方法同实施例2。结果如表19所示，表明特声波作用可显著提高胰岛素水凝胶制剂的透大鼠皮肤作用。
表19 特声波促胰岛素透大鼠皮肤的结果
Figure PCTCN2020095399-appb-000027
实施例21 大鼠体内促胰岛素水凝胶透皮药效评价
取实施例19制备的胰岛素水凝胶制剂，剪裁至与超高频体声波谐振器器件相应的尺寸。将剪裁好的胰岛素水凝胶制剂与超高频体声波谐振器的表面相贴，构成胰岛素药物水凝胶透皮贴剂。将其贴于用乙醚麻醉的大鼠腹部，分别在不加功率激活超高频声波谐振器产生体声波和加功率的条件上测定胰岛素的透皮效果，分别为对照和测试样品。加功率条件为500mW，2.58GHz，0.5S加压脉冲，0.5S间隔。释药90分钟。在2、4、6、8、 10、12小时检测血糖的变化，与正常麻醉不给药组的同步血糖对比，另设等量静注的胰岛素组对阳性对照。每组实验重复3次。结果如表20所示。
表20 特声波促胰岛素水凝胶制剂透大鼠皮肤的在体实验结果
Figure PCTCN2020095399-appb-000028
实验发现，相同条件下，与不加功率对照组相比，加功率组可显著降低动物体内血糖含量，说明透皮效果显著；与静注给药组相比，加功率组具有持续释药的效果，在10小时内均能维持显著的降血糖效果，而静注给药组在2小时达到最大降糖效果后，第4小时后即失去有效的降血糖作用。可见，本本发明的特声波透皮制剂的降糖效果具有高效和长效的特点，与现有技术相比优势明显。
实施例22 促氟比洛芬水凝胶的RC-1000膜透膜
取市售水凝胶制剂氟比洛芬巴布膏(北京泰德制药)，剪裁至与超高频体声波谐振器器件相应的尺寸。将剪裁好的氟比洛芬巴布膏背衬与超高频体声波谐振器的表面相贴，释药面与RC-1000膜(JMD38，Solarbio)相贴，膜的另一面与接收池紧密接触，在接收池中注入PBS 300ul。分别在不加功率激活超高频声波谐振器和加功率的条件上测定胰岛素的透皮 效果，分别为对照和测试样品。加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。分别于30、60、90和120分钟取样测定氟比洛芬的透皮效率。
氟比洛芬的检测方法如下：取本品，精密称定，加溶剂[乙腈-水(45∶55)]溶解并稀释制成每1ml中约含2.0mg的溶液作为对照品溶液，不同时间取样为供试品。用十八烷基硅烷键合硅胶为填充剂；以乙腈-水-冰醋酸(35∶60∶5)为流动相；检测波长为254nm。精密量取对照品溶液与供试品溶液各20μl，分别注入液相色谱仪，记录色谱图至主成分峰保留时间的3倍。按外标法以峰面积计算。
结果如表21所示，表明特声波作用可显著提高氟比洛芬水凝胶制剂的透膜作用。
表21 特声波促氟比洛芬水凝胶透RC-1000膜的结果
Figure PCTCN2020095399-appb-000029
实施例23 促氟比洛芬水凝胶的透大鼠皮
取市售水凝胶制剂氟比洛芬巴布膏(北京泰德制药)，剪裁至与特声波激发器件相应的尺寸。将剪裁好的氟比洛芬巴布膏背衬与超高频体声波谐振器的表面相贴，释药面与大鼠腹部皮肤密封，鼠皮另一面与接收池紧密接触，收集池注入300ul PBS。分别在不加功率和加功率的条件上测定氟比洛芬的透皮效果，分别为对照和测试样品。加功率条件为500mW，频率2.58GHz，0.5S加压脉冲，0.5S间隔。分别于30、60、90和120分钟 取样测定氟比洛芬的透皮效率。
测定结果如表22所示，表明特声波作用可显著提高氟比洛芬水凝胶制剂的透膜作用。
表22 特声波促氟比洛芬水凝胶透大鼠皮肤的结果
Figure PCTCN2020095399-appb-000030
本发明提供了新的利用超高频谐振器产生体声波来实现生物活性物质的透皮，特别是对不易或不可透皮药物分子的透皮给药方法和装置。发明人出乎意料地发现超高频谐振器产生体声波能够有效地将小分子化合物和蛋白质有效地通过半透膜，甚至能够通过动物体的皮肤，由此提供了安全地和方便地递送小分子化学药、多肽药物以及抗体及疫苗等生物药的方法和装置。发明人还解决了将存在于液体中的活性物质制成给药组合物和装置的方法，包括通过用半透明膜进行封装。
虽然关于本发明的示例实施例及其优点已经详细说明，应当理解在不脱离本发明的精神和所附权利要求限定的保护范围的情况下，可以对这些实施例进行各种变化、替换和修改。此外，本发明的应用范围不局限于说明书中描述的特定实施例的工艺、机构、制造、物质组成、手段、方法及步骤。因此，本发明所附权利要求旨在将这些工艺、机构、制造、物质组成、手段、方法或步骤包含在其保护范围内。

Claims (33)

  1. 将生物活性剂通过透皮释放给予患者的方法，所述方法包括：
    (1)提供含有生物活性剂的储库，所述储库用于容纳含有活性剂的溶液、悬浮液或凝胶，
    (2)激活一个或多个超高频声波谐振器，在所述溶液、悬浮液或凝胶中产生频率为约0.5-50GHz的体声波，使得所述生物活性剂进入或透过患者的皮肤。
  2. 如权利要求1所述的方法，其中储库容纳溶液或悬浮液或凝胶。
  3. 如权利要求1所述的方法，其中所述溶液或悬浮液或凝胶与患者的皮肤接触。
  4. 如权利要求1所述的方法，其中所述溶液或悬浮液或凝胶通过半透膜与患者的皮肤接触。
  5. 如权利要求1所述的方法，其中所述生物活性剂的分子量为200～1000000道尔顿。
  6. 如权利要求1所述的方法，其中所述生物活性剂为小分子化合物、多肽、蛋白质例如胰岛素、寡核苷酸、核酸和多糖。
  7. 如权利要求1所述的方法，其中所述超高频声波谐振器为薄膜体声波谐振器或固态装配型谐振器。
  8. 如权利要求1所述的方法，其中所述超高频声波谐振器与患者的皮肤的距离为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。
  9. 权利要求1的方法，其中所述超高频声波谐振器的体声波产生区域面积为约1000-50000μm 2，优选为约5000-20000μm 2。
  10. 如权利要求1所述的方法，其中所述超高频声波谐振器产生的体声波的功率为约0.1-50W，优选为0.2-10W，更优选为0.5-5W。
  11. 一种将活性剂通过透皮释放给予患者的装置，其包括
    储库，所述储库容纳含有生物活性剂的溶液或悬浮液，或容纳含有生物活性剂的凝胶特别是水凝胶；
    设置在所述储库的底部的一个或多个超高频体声波谐振器，所述一个 或多个超高频体声波谐振器设置为可在所述溶液或悬浮液中产生频率为约0.5-50GHz的体声波。
  12. 权利要求11所述的装置，其中所述储库的上表面具有半透膜。
  13. 权利要求11所述的装置，其还包括外壳，所述储库可装卸地与外壳连接。
  14. 权利要求11所述的装置，其中所述储库的深度为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。
  15. 权利要求11所述的装置，其中所述超高频声波谐振器产生的体声波的功率为约0.1-50W，优选为0.2-10W，更优选为0.5-5W。
  16. 如权利要求11所述的装置，其中所述生物活性剂的分子量为200～1000000道尔顿。
  17. 权利要求11所述的装置，其中所述超高频声波谐振器为薄膜体声波谐振器或固态装配型谐振器，例如为厚度伸缩振动模式声波谐振器。
  18. 一种透皮给药组合物，其包括
    容纳含有活性剂的溶液或悬浮液的储库；
    可装卸地设置在所述储库的底部的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器设置为可在所述溶液或悬浮液中产生频率为约0.5-50GHz的体声波。
  19. 权利要求18所述的透皮给药组合物，其中所述储库的上表面具有半透膜。
  20. 如权利要求18所述的透皮给药组合物，其中所述生物活性剂的分子量为200～1000000道尔顿。
  21. 如权利要求18所述的透皮给药组合物，其中所述生物活性剂为小分子化合物例如氟比洛芬、多肽、蛋白质例如胰岛素、寡核苷酸、核酸和多糖。
  22. 如权利要求18所述的透皮给药组合物，其中所述超高频声波谐振器为薄膜体声波谐振器或固态装配型谐振器，例如为厚度伸缩振动模式的声波谐振器。
  23. 如权利要求18所述的透皮给药组合物，其中所述储库的厚度为约 0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。
  24. 如权利要求18所述的透皮给药组合物，其中所述超高频声波谐振器的体声波产生区域面积为约1000-50000μm 2，优选为约5000-20000μm 2。
  25. 如权利要求18所述的透皮给药组合物，其中所述超高频声波谐振器产生的体声波的功率为约0.1-50W，优选为0.2-10W，更优选为0.5-5W。
  26. 一种透皮释放的药物制剂，其包括：
    含有活性剂的凝胶特别是水凝胶；
    与所述凝胶的底部接触的可装卸的一个或多个超高频体声波谐振器，所述一个或多个超高频体声波谐振器设置为在凝胶中产生频率为约0.5-50GHz的体声波。
  27. 权利要求26所述的药物制剂，其中凝胶的上表面具有半透膜。
  28. 权利要求26所述的药物制剂，其中所述药物制剂的上表面具有皮肤粘附层，其可包含选自以下的聚合物膜：聚丙烯酸、壳聚糖、果胶、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羟乙基纤维素(HEC)、或其它皮肤粘附性聚合物。
  29. 权利要求26所述的药物制剂，其中所述凝胶的底部具有支持层，优选的，所述超高频谐振器可装卸地装配在所述支持层。
  30. 权利要求26所述的药物制剂，其中所述凝胶的厚度为约0.1-20mm，优选为0.5-15mm，最优选是约1-10mm。
  31. 权利要求26所述的药物制剂，其中所述超高频声波谐振器的体声波产生区域面积为约1000-50000μm 2，优选为约5000-20000μm 2。
  32. 权利要求26所述的药物制剂，其中所述生物活性剂的分子量为200～1000000道尔顿。
  33. 如权利要求26所述的药物制剂，其中所述生物活性剂为小分子化合物如氟比洛芬、多肽、蛋白质如胰岛素、寡核苷酸、核酸和多糖。
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