CN112057415A

CN112057415A - Gel preparation for transdermal administration and use thereof

Info

Publication number: CN112057415A
Application number: CN202010519410.2A
Authority: CN
Inventors: 段学欣
Original assignee: Hydermore Pharmaceutical Technology Co ltd
Current assignee: Hydermore Pharmaceutical Technology Co ltd
Priority date: 2019-06-10
Filing date: 2020-06-09
Publication date: 2020-12-11

Abstract

The present invention provides transdermal gel formulations and uses thereof, including methods and devices for administering biologically active agents to a patient via transdermal delivery. The preparation and the application provided by the invention can realize the transdermal penetration of substances which are difficult to penetrate or cannot penetrate, including but not limited to small molecular chemical drugs, polypeptide drugs, antibodies, vaccines and other bioactive substances.

Description

Gel preparation for transdermal administration and use thereof

The present application claims priority from the following chinese patent applications: application No. 201910496333.0 entitled "transdermal gel formulation and uses thereof", filed 2019, 6/10/2019, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to drug delivery methods and devices. More particularly, the present invention relates to methods and formulations for enhancing transdermal drug delivery using bulk acoustic waves generated by a uhf resonator. The method of the invention can realize the transdermal penetration of substances which are difficult to penetrate or can not penetrate, including but not limited to small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other bioactive substances.

Background

The skin is covered on the surface layer of the human body and is directly contacted with the external environment, so that external substances are prevented from entering the human body, and the skin has an important protection function. The skin is formed by tightly combining epidermis and dermis. The epidermis is composed of multiple layers of flat epithelia, including cuticle, stratum lucidum, stratum granulosum and stratum germinatum from superficial to deep. The stratum corneum is composed of multiple layers of keratinized epithelial cells (nuclei and organelles disappear, the cell membranes are thick) and intercellular lipids, is non-living and waterproof, has the functions of preventing tissue fluid from flowing out, resisting abrasion, preventing infection and the like, and is a main barrier for absorbing exogenous substances through the skin. The dermis is composed of compact connective tissue, and is provided with a nipple layer and a reticular layer from the shallow to the deep, wherein the reticular layer is connected with subcutaneous tissue, and is internally provided with abundant collagen fibers, elastic fibers and reticular fibers which are mutually interwoven into a net, so that the skin has larger elasticity and toughness.

The general term "transdermal", as used herein, refers to the delivery 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 the local tissue or systemic circulatory system without substantially cutting or piercing the skin, such as by cutting with a surgical knife or piercing the skin with a hypodermic needle. The advantages of transdermal drug delivery systems are represented by: the drug absorption is not influenced by factors such as pH, food, transport time and the like in the digestive tract; the first pass effect of the liver is avoided; adverse reactions caused by overhigh blood concentration due to too fast absorption are overcome; the drug administration speed can be continuously controlled, the drug administration is flexible, and the like.

In a skin drug delivery system, the epidermis, especially the stratum corneum, is the main barrier for drugs to enter the body, and researches show that only a few drugs have excellent skin permeability, and most drugs cannot easily penetrate the skin of a human body, namely the effective and selective barrier. The epidermis, and in particular the stratum corneum, is the primary barrier layer, and once its protective function is lost, large quantities of water-soluble, non-electrolyte molecules diffuse into the systemic circulation at a rate that is thousands of times faster, so that the promotion of transdermal absorption of the drug is primarily a reduction in the barrier layer's resistance.

At present, the technology for dynamically opening the compact structure of the stratum corneum to realize transdermal drug delivery mainly comprises chemical penetration promotion, physical penetration promotion (conductance, microneedles) and the like. The chemical penetration promotion is realized mainly by a substance which can reversibly change the barrier function of the skin stratum corneum without damaging any active cell, enhance the transdermal capacity of the drug and improve the transdermal quantity of the drug. The chemical penetration enhancer can be integrated with a pharmaceutical preparation, but irritation such as skin red swelling and pain can be generated when the dosage is larger or the time is longer, and the compatibility with the pharmaceutical ingredients is also an important factor for restricting the application of the pharmaceutical preparation.

Common single physical penetration-promoting methods include microneedle, electret, ion, electroporation, laser, magnetic field introduction, and thermal perforation. The micro-needle permeation promotion is that a transdermal patch consisting of dozens to hundreds of hollow or solid micro-needles is attached to the skin, penetrates the stratum corneum barrier and produces micro-channels on the epidermis layer, and the drug enters systemic circulation through the micro-channels, can promote the drug to permeate to a specific part through the skin, and is suitable for macromolecular drugs (such as polypeptide, protein, vaccine and the like with low skin permeability). The electroporation technology is a method for improving the permeability of cells and tissue membranes by changing the directional arrangement of skin stratum corneum lipid molecules under the action of instantaneous high-voltage pulse current to increase the disordered structure of lipid bilayers to form transient and reversible hydrophilic pore canals, and is suitable for small-molecule drugs (such as insulin) with better ionization performance, but is limited in popularization due to the dependence on a charged device and energy characteristics. The laser technology is a physical permeation promoting technology which utilizes the impact of photomechanical waves formed by laser impact target substances on skin to generate energy to ablate or degrade horny layers, change the molecular arrangement of organism tissues and form dense pore canals so as to promote the transdermal absorption of macromolecular drugs. Magnetic field introduction permeation promotion is a physical technology for improving the transdermal permeability of a medicament by applying a magnetic field. The hot perforation technique is a technique of forming hydrophilic channels in the stratum corneum using a pulse heating method to increase skin permeability. Although the magnetic field introduction and thermal perforation technology can improve the percutaneous permeability of the medicine, the complexity and high cost of the manufacturing are the problems to be overcome.

The method of introducing drugs by ultrasound has been reported, the specific action mechanism of which has not been fully elucidated so far, and the mainstream view at present considers that cavitation is the most dominant action mechanism of ultrasound penetration promotion. Cavitation refers to the process of gas vacuole formation, expansion, contraction and disintegration in the propagation of ultrasonic waves in a medium. Existing research results indicate that lower frequencies are better for cavitation [ Hideo U, et al, pharmaceutical bullets, 2009, 32 (32); 916-.

The ultra-high frequency sound wave is ultra-high frequency longitudinal sound wave with the frequency of more than 0.3GHz, is mainly used in the field of communication, and is never applied to the permeation promotion application of organisms due to the well-known permeation promotion effect of low-frequency ultrasonic waves in the prior art. Researches of Zhongcheng et al in 2017 show that ultrahigh-frequency special sound waves (1.6GHz and 300mW) can instantaneously form nanopores in cell membranes, so that drug molecules, DNA fragments and gene lipid particles penetrate through the cell membranes and enter cytoplasm [ Zhongcheng et al, small 2017,1602962 ]. Further research results show that the liposome can be used for drug loading and drug release of double-layer lipid membranes and liposomes (Zhongzhixin, etc., Angew. chem. int. Ed. 10.1002/anie.201810181). However, the published literature is limited to the action of double-layer liposome on cell membranes or similar cell membranes, and the stratum corneum for limiting the transdermal action is formed by tightly packing multiple layers of keratinized epithelial cells (nuclei and organelles disappear, the cell membranes are thick) and intercellular lipids, so that the technology is not life-free and watertight, and has great difference in composition, density and thickness and the structure of the cell membranes, so that the possibility and safety of the application of the technology in the aspect of physical transdermal promotion cannot be judged.

There is also a need in the art for more effective and safe transdermal delivery methods and formulations.

Disclosure of Invention

The invention provides a novel method, a device and a preparation for realizing transdermal delivery of bioactive substances by using a bulk acoustic wave generated by an ultrahigh frequency resonator, in particular to transdermal delivery of difficult or impossible transdermal drug molecules. The method provided by the invention can effectively and safely deliver small-molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other biological drugs.

In particular, the present invention provides a method of administering a biologically active agent to a patient via transdermal delivery, the method comprising:

(1) providing a reservoir (reservoir) containing a biologically active agent for holding a solution, suspension or gel containing the active agent,

(2) activating one or more ultra-high frequency acoustic wave resonators to generate bulk acoustic waves in the solution, suspension or gel at a frequency of about 0.5-50GHz such that the bioactive agent enters or permeates the skin of the patient.

The term "transdermal" as used herein refers to the delivery of a drug into and/or through the skin for local or systemic therapeutic purposes.

Patients refer to humans or other animals, including, without limitation, other primates such as chimpanzees and other apes and monkeys; farm raised animals such as cattle, sheep, pigs, goats and horses; domestic animals such as dogs and cats; laboratory 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, geese, and the like.

Biologically active agents refer to compositions of matter or mixtures containing an active agent or drug that are 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.

In the method of the present invention, the molecular weight of the bioactive agent is in the range of 200 to 1000000 daltons.

In the methods of the invention, the bioactive agent may also be delivered by attachment to a carrier. The support may be any solid matrix used in biotechnology for immobilization. Such a carrier may be a particle, a sheet, a membrane, a gel, a filter, a microtiter strip, a tube or a plate. Specific supports of interest include silica, glass, inorganic supports such as metal nanoparticles or alumina, organic supports such as polymeric supports (e.g., polystyrene). Preferably, the solid support is a polymer particle, in particular a polymer microparticle, which may have a diameter of 50nm to 500 μm, for example 100nm to 100 μm.

Examples of "bioactive agents" include, but are not limited to, Luteinizing Hormone Releasing Hormone (LHRH); LHRH analogs (e.g., goserelin, leuprolide, buserelin, triptorelin, gonadorelin and napfarelin, menotrophins (FSH) and LH)); a vasopressin; desmopressin; adrenocorticotropic hormone (ACTH); ACTH analogs such as ACTH (1-24); a calcitonin; a vasopressin; deaminated [ Val4, D-Arg8] arginine vasopressin; an alpha interferon; an interferon-beta; gamma interferon; erythropoietin (EPO); granulocyte macrophage colony stimulating factor (GM-CSF); granulocyte colony stimulating factor (G-CSF); interleukin-10 (IL-10); glucagon; GHRF (GHRF); insulin; an insulinotropic agent; a calcitonin; octreotide; endorphins; TRN; NT-36 (chemical name: N- [ [ (S) -4-oxo-2-azetidinyl ] carbonyl ] -L-histidyl-L-prolinamide); lipricin; alpha ANF; β MSH; somatostatin; bradykinin; a growth hormone; platelet-derived growth factor releasing factor; chymopapain; cholecystokinin; chorionic gonadotropin; epoprostenol (platelet aggregation inhibitor); glucagon; bivalirudin; an interferon; an interleukin; menotropins (urofollitropin (FSH) and LH); oxytocin; a streptokinase; tissue plasminogen activator; urokinase; ANP; inhibitors of ANP clearance; BNP; VEGF; an angiotensin II antagonist; an antidiuretic agonist; a bradykinin antagonist; ceredase; CSI's; calcitonin Gene Related Peptide (CGRP); enkephalin; a FAB fragment; IgE peptide inhibitory factor; IGF-1; a neurotrophic factor; a colony stimulating factor; parathyroid hormone and agonists; parathyroid hormone antagonists; a prostaglandin antagonist; pentigtide; protein C; protein S; a renin inhibitor; thymosin alpha 1; thrombolytic drugs; TNF; a vasopressin antagonist analog; alpha-1 antitrypsin (recombinant); TGF-beta; fondaparinux; adefovir dipivoxil; to heparin; defibrinide; enoxaparin; hirudin; nadroparin; heparin; tinzaparin; pentosan polysulfate; oligonucleotides and oligonucleotide derivatives such as formivirsen; alendronic acid; a chlorophosphonic acid; etidronic acid; ibandronic acid; incadronic acid; pamidronic acid; risedronic acid; tiludronic acid; zoledronic acid; argatroban; RWJ 445167; RWJ-671818; fentanyl; remifentanil; sufentanil; alfentanil; lofentanil; carfentanil and mixtures thereof.

The method of the present invention is particularly suitable for use with pharmaceutically active agents that are not readily or transdermally permeable. For example, bulky active agents such as proteins. The protein may include, among others, cytokines, 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 or can not pass through the usual transdermal preparations due to physical properties such as hydrophobicity.

In the method of the invention, the active agent is present in a solution or suspension or gel. In one aspect of the invention, the active agent is present in a gel.

In yet another aspect of the invention, the gel is in contact with the skin of the patient. In another of its aspects, the gel is in contact with the patient's skin through a semi-permeable membrane.

In the method of the invention, the solution or suspension or gel is a solvent in which each of the bioactive agents is soluble. In one aspect of the invention, the solvent contained in the solution or suspension or gel 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, and the like. In the method of the invention, the solution, suspension or gel may contain, in addition to the biologically active agent, an inert filler; a penetration enhancer; excipients and other pharmaceutical products or conventional components of transdermal devices known in the art.

In the method of the present invention, the semi-permeable membrane is one through which the active agent cannot freely diffuse. Semipermeable membranes useful in the methods of the invention are referred to as a variety of natural and artificial membranes known in the art having selective retention of compounds of different molecular weights, including, but not limited to, collodion semipermeable membranes, parchment semipermeable membranes, polymeric semipermeable membranes such as cellulose ester membranes, regenerated cellulose membranes, polypropylene membranes, and the like.

The gels useful in the methods of the invention can be various natural or polymeric gels, such as hydrogels (hydrogels). The hydrogel may be naturally occurring (e.g., agarose, dextran, chitin, cellulose-based compounds, starch, derivatized starch, etc.) or synthetically prepared or modified (e.g., polyethylene glycol PEG). A hydrogel is a substance that contains a three-dimensional network of macromolecules such that it swells in the presence of water, collapses in the absence of water (or by reducing the amount of water), but is insoluble in water. Crosslinking between adjacent macromolecules results in water insolubility of the hydrogel. Although the dry state of the macromolecular materials suitable for use in the present invention are sometimes referred to in the polymer industry as "xerogels" and the hydrated state as "hydrogels", for the purposes of this patent application, the term "hydrogel" refers to a macromolecular material, whether anhydrous or hydrated. Hydrogels are most characterized in that the material retains a regular shape, whether in the dehydrated or hydrated state. Thus, if the hydrogel is substantially spherical in the dehydrated state, it will be spherical in the hydrated state.

The hydrogel employed in the present invention is preferably a water-based hydrogel because of its high water content and biocompatibility. Polymers in hydrogels employed in the present invention include, but are not limited to, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), Methylcellulose (MC), hydroxyethyl methylcellulose (HEMC), ethyl hydroxyethyl cellulose (EHEC), carboxymethyl cellulose (CMC), poly (vinyl alcohol), poly (ethylene oxide), poly (2-hydroxyethyl methacrylate), poly (n-vinyl pyrrolidone), and poloxamers. Preferred polymeric materials are cellulose derivatives.

The active agent may be bound to the hydrogel by: the active agent diffuses aqueous into the macromolecular network and the macromolecular material is then dried, thereby immobilizing the active agent in the hydrogel. The active agent may be incorporated into the hydrogel either as a homogeneously dispersed and completely absorbed into the resulting hydrogel or as a partially dispersed within only a portion of the hydrogel particles. Alternatively, or in the alternative, the active agent is bound to the hydrogel by virtue of an ionic or covalent bond formed between the two components, the active agent being contained predominantly in the hydrogel matrix or bound (e.g., bonded) to the surface of the hydrogel structure. Upon exposure of the hydrogel to an aqueous environment, the macromolecular network expands, thereby releasing the active agent, the active agent.

In the methods of the invention, the bioactive agent may be present in the solution, suspension or gel in any possible amount. Suitable amounts may be found in reference to transdermal formulations known in the art or may be tested by known methods. For example, since the method of the present invention can adjust the amount of active agent that is transdermally administered by controlling various parameters of the generation of sound waves by the UHF acoustic wave resonator, the appropriate amount in solution, suspension or gel can be experimentally detected and selected to ensure that a therapeutically effective and safe amount of active agent is administered to the patient.

In the methods and devices of the present invention, a reservoir (reservoir) containing a bioactive agent is employed. The reservoir is adapted to hold a solution, suspension or gel, or to hold a gel. The gel may be added directly into the reservoir and then encapsulate the upper surface of the reservoir with a semi-permeable membrane, or may be provided in a pre-packaged form. The material of the encapsulation may be a semi-permeable membrane or the like. For example, the reservoir has four borders for containing the gel. As another example, the reservoir has two-four rims or slots for receiving gel sheets or gel blocks. In one aspect of the invention, the reservoir is the gel, such as gel sheets and gel blocks.

In the method of the present invention, bulk acoustic waves are generated in solution at ultra high frequencies (about 0.5-50GHz) using ultra high frequency acoustic resonators. Particles (e.g., bioactive agents) in the bulk acoustic wave region caused by the ultra-high frequency are subjected to a combination of fluid drag force (Stokes drag force), inertial drag force (inertial lift force) caused by laminar flow, and acoustic radiation force (acoustic radiation force) caused by acoustic wave attenuation. Under appropriate conditions (properties of the solution and the particles, intensity of the bulk acoustic wave, distance of movement of the particles, etc.), the bulk acoustic wave induces a flow of the particles in the solution in the direction of propagation of the acoustic wave, is able to penetrate through the skin into the interior of the skin, and does not cause irreversible damage to the skin.

The ultrahigh frequency acoustic wave resonator adopted by the invention can generate high-frequency (about 0.5-50GHz) vibration to induce bulk acoustic waves with corresponding frequencies in a solution. In one aspect of the present invention, the ultra-high frequency acoustic resonator is a Film Bulk Acoustic Resonator (FBAR) or a solid-state fabricated resonator (SMR), preferably a solid-state fabricated resonator. In still another aspect of the present invention, the uhf acoustic resonator is an acoustic resonator of a thickness extensional vibration mode, and the thin film layer of piezoelectric material is grown in a vertical direction, and the vibration is excited by coupling a d33 piezoelectric coefficient to a vertical electric field. The ultrahigh frequency acoustic wave resonator adopted by the invention can generate localized acoustic flow at the interface of the device and the liquid without the help of a coupling medium or a structure. The acoustic wave resonator comprises an acoustic wave reflecting layer, a bottom electrode layer, a piezoelectric layer and a top electrode layer which are sequentially arranged from bottom to top. The overlapped area of the bottom electrode layer, the piezoelectric layer, the top electrode layer and the acoustic wave reflecting layer forms a bulk acoustic wave generating area. The top surface of the ultrahigh frequency acoustic wave resonator is configured on the wall of the fluid channel, and bulk acoustic waves with the propagation direction vertical to the wall are generated to the opposite wall; the region constituted by the top surface may be referred to as the bulk acoustic wave action region. The thickness of the piezoelectric layer of the ultrahigh frequency acoustic wave resonator of the invention ranges from about 1nm to 2 um. The UHF acoustic wave resonator of the present invention has a frequency of about 0.5-50GHz, preferably about 1-10 GHz.

In the present invention, the shape of the acoustic wave action region may be any shape. In one aspect of the present invention, the bulk acoustic wave generating region of the UHF acoustic resonator has a width of about 50-300 μm, such as about 70-150 μm. In yet another aspect of the present invention, the bulk acoustic wave generation region area of the UHF acoustic wave resonator is about 1000-50000 mu m²Preferably about 5000-²。

In one aspect of the invention, in the method of administering a biologically active agent to a patient via transdermal delivery, the UHF acoustic resonator is located at a distance of about 0.1-20mm, preferably 0.5-15mm, and most preferably about 1-10mm from the patient's skin.

The inventor of the present application has unexpectedly found that when the distance between the uhf acoustic wave resonator and the skin of the patient is about 0.1 to 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 yet another aspect of the invention, the gel has a thickness of about 0.1 to 20mm, preferably 0.5 to 15mm, and most preferably about 1 to 10 mm. When the medicine is administrated, the upper surface of the gel is in contact with the skin of a patient, and the UHF bulk acoustic wave resonator is arranged to be in contact with the lower surface of the gel, so that the thickness of the gel is equivalent to the distance between the UHF bulk acoustic wave resonator and the skin of the patient.

In one aspect of the invention, the transdermal efficiency of the bioactive agent can be modulated by the power of the bulk acoustic wave. And the micro-fluidic equipment adjusts the power of the bulk acoustic wave generated by the ultrahigh frequency acoustic wave resonator through a power adjusting device. The output power of the power regulating device is about 0.1-50W, preferably 0.2-10W, more preferably 0.5-5W. The higher the power, the higher the transdermal efficiency, within certain parameters.

The bulk acoustic wave generated by the ultrahigh frequency acoustic wave resonator is driven by the signal of the high frequency signal generator. The pulsed voltage signal driving the resonator may be driven with pulse width modulation, which may produce any desired waveform, such as a sine wave, square wave, sawtooth wave, or triangle wave. The pulsed voltage signal may also have amplitude or frequency modulated start/stop capability to start or cancel bulk acoustic waves.

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

an active agent-containing gel or a reservoir containing the active agent-containing gel; the gel is typically in contact with the patient's skin at its top, i.e. its upper surface;

one or more UHF bulk acoustic resonators in contact with the bottom of the gel, the one or more UHF bulk acoustic resonators being arranged to generate bulk acoustic waves in the gel having a frequency of about 0.5-50 GHz. The propagation direction of the bulk acoustic wave generated in the gel by the UHF bulk acoustic wave resonator is towards the top of the gel, i.e. the surface in contact with the patient's skin.

In one of the inventions, the gel is a hydrogel, in particular a water-based hydrogel.

In one aspect of the invention, the upper surface of the gel has a semi-permeable membrane through which the active agent is not free to diffuse. In one of its aspects, the outer surface of the semi-permeable membrane may also have a peelable sealing membrane that is peeled off prior to use (contact with the patient's skin).

In one of its aspects, the upper surface of the gel also has a skin adhesive 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-adherent polymers. In yet another aspect of the invention, the gel itself comprises a skin-adherent polymer.

In one aspect of the invention, the device further comprises a housing, the gel and/or the uhf bulk acoustic wave resonator each being removably connected to the housing. For example, the housing comprises a reservoir suitable for holding a gel as described previously; the UHF bulk acoustic resonator is removably embedded in the bottom of the reservoir such that the top of the UHF bulk acoustic resonator is in contact with the bottom of the gel. In other aspects of the invention, the housing has means, such as a strap or the like, adapted to be secured to the human or animal body such that the upper surface of the gel remains in engagement with the skin.

In one aspect of the invention, the uhf resonator in the device has a circuit that receives a pulsed voltage signal. For example, the uhf resonator has a circuit for receiving a connection to an external hf signal generator and an interface, which is provided on the device housing. For another example, the uhf resonator has a circuit that accepts a radio frequency signal. When the active agent requires chronic or timed administration, the device further comprises a timed emission signal system that excites the UHF bulk acoustic wave resonator for a specified time or period of time.

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

In one aspect of the invention, the bioactive agent has a molecular weight of 200 to 1000000 daltons.

In one aspect of the invention, the ultra-high frequency acoustic wave resonator in the device is a film bulk acoustic wave resonator or a solid-state fabricated resonator, such as an acoustic wave resonator of thickness extensional vibration mode.

In one aspect of the invention, the gel has a thickness of about 0.1 to 20mm, preferably 0.5 to 15mm, and most preferably about 1 to 10 mm. When the medicine is administrated, the upper surface of the gel is in contact with the skin of a patient, so that the thickness of the gel is equivalent to the distance between the ultrahigh frequency sound wave resonator arranged at the bottom of the gel and the skin of the patient.

In one aspect of the invention, the bulk acoustic wave generation region area of the UHF acoustic resonator in the device is about 1000-50000 mu m²Preferably about 5000-²。

In one aspect of the invention, the bulk acoustic wave generated by the UHF acoustic resonator in the device has a power of about 0.1-50W, preferably 0.2-10W, and more preferably 0.5-5W.

In one aspect of the present invention, there is also provided a transdermal drug delivery formulation comprising:

a gel containing an active agent; the gel is typically in contact with the patient's skin at its top, i.e. its upper surface;

one or more removable UHF bulk acoustic wave resonators in contact with the bottom of the gel, the one or more UHF bulk acoustic wave resonators being arranged to generate bulk acoustic waves in the gel at a frequency of about 0.5-50 GHz. The propagation direction of the bulk acoustic wave generated in the gel by the UHF bulk acoustic wave resonator is towards the top of the gel, i.e. the surface in contact with the patient's skin.

In one aspect of the invention, the upper surface of the gel has a semi-permeable membrane through which the active agent is not free to diffuse.

In one aspect of the invention, the upper surface of the gel 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-adherent polymers. In yet another aspect of the invention, the gel itself comprises a skin-adherent polymer.

In one aspect of the invention, the outermost surface of the pharmaceutical formulation may also have a peelable sealing film that is peeled off prior to use (contact with the skin of a patient).

In one aspect of the invention, the gel has a support layer on the bottom, the UHF resonator being removably mounted on the support layer. The support layer is made of Polydimethylsiloxane (PDMS), for example. The support layer is, for example, a polymer film layer having a relatively high hardness.

In one aspect of the invention, the UHF resonator in the pharmaceutical formulation has circuitry for receiving a pulsed voltage signal. For example, the uhf resonator has a circuit for receiving a connection to an external hf signal generator and an interface, which is provided on the device housing. For another example, the uhf resonator has a circuit that accepts a radio frequency signal. When the active agent requires chronic or timed administration, the device further comprises a timed emission signal system that excites the UHF bulk acoustic wave resonator for a specified time or period of time.

In one aspect of the invention, the biologically active agent in the pharmaceutical formulation is a small molecule compound, a polypeptide, a protein, an oligonucleotide, a nucleic acid, and a polysaccharide.

In one aspect of the invention, the bioactive agent in the pharmaceutical preparation has a molecular weight of 200-1000000 daltons.

In one aspect of the invention, the ultra-high frequency acoustic wave resonator in the pharmaceutical preparation is a film bulk acoustic wave resonator or a solid assembled resonator, such as an acoustic wave resonator with thickness extensional vibration mode.

In one aspect of the invention, the bulk acoustic wave generation region area of the UHF acoustic resonator in the composition is about 1000-50000 mu m²Preferably about 5000-²。

In one aspect of the invention, the bulk acoustic wave generated by the UHF acoustic resonator in the composition has a power of about 0.1W to about 50W, preferably 0.2W to about 10W, and more preferably 0.5W to about 5W.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.

FIG. 1 shows an exemplary experimental setup of the present invention.

Fig. 2 shows an exemplary uhf acoustic wave resonator of the present invention.

Fig. 3 shows a schematic view of an exemplary embodiment of a pharmaceutical formulation of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of the present invention.

Example 1 Experimental setup and Material preparation

The experimental setup was as shown in FIG. 1. The device comprises an upper well and a lower well which are surrounded by Polydimethylsiloxane (PDMS) material walls and have adjustable heights. The well below is connected with a circuit board with an ultrahigh frequency acoustic wave resonator in a sealing way to form a liquid supply pool capable of containing liquid or gel. In the experiment, the volume of the feed reservoir was adjusted to about 30. mu.L and the height was adjusted to about 1 mm. The top of the liquid supply pool is sealed by a semi-permeable membrane and/or a mouse skin. Adding solution or gel containing active substance into the liquid supply tank. The resonator may generate bulk acoustic waves in the liquid in the chamber that propagate to the top at a frequency of about 0.5-50 GHz. The upper well is separated from the fluid supply pool by a semi-permeable membrane and/or an animal skin sample according to different experiments, and PBS can be added into the upper well for receiving active substances permeating from the fluid supply pool, and the upper well is also called a receiving pool.

FIG. 2 is a photograph of an exemplary UHF acoustic wave resonator, i.e., a real object of an ultra-high frequency acoustic wave, in the method and apparatus of the present invention, which generates bulk acoustic waves having an area of about 15000-². The left diagram of fig. 2 shows the proportion of the uhf acoustic resonator device to the coin. The right diagram of fig. 2 shows the area and pattern of the bulk acoustic wave generated by the uhf acoustic wave resonator (the pattern illustrated in the figure is pentagonal).

Fig. 3 is a schematic illustration of an exemplary transdermal drug delivery formulation provided by the present invention.

Wherein the transdermal drug delivery formulation comprises a gel 10 containing an active agent; a plurality of UHF bulk acoustic resonators 20 in contact with the bottom of the gel, the one or more UHF bulk acoustic resonators generating bulk acoustic waves at the gel at a frequency of about 0.5-50 GHz. The bottom layer of the gel has a support layer 40 to which the uhf resonator is removably mounted. The gel is typically in contact with the patient's skin at its top, i.e. its upper surface. The bulk acoustic wave resonator is arranged such that the propagation direction of the bulk acoustic waves generated in the gel is towards the top of the gel, i.e. the surface in contact with the skin of the patient. The upper surface of the gel has a semi-permeable membrane 30 through which the active agent is not free to diffuse. The outer surface of the semi-permeable membrane may also have a peelable closing membrane 50.

Preparing an ultrahigh frequency acoustic wave resonator:

the UHF acoustic wave resonator was prepared according to the reported method (Zhixin Zhang et al, Small 2017,13, 1602962-. The ultrahigh frequency acoustic wave resonator comprises an acoustic wave reflecting layer, a bottom electrode layer, a piezoelectric layer and a top electrode layer which are sequentially arranged from bottom to top. The overlapped area of the bottom electrode layer, the piezoelectric layer, the top electrode layer and the acoustic wave reflecting layer forms a bulk acoustic wave generating area. The top surface of the ultrahigh frequency acoustic wave resonator is configured at the bottom of the PDMS well, and bulk acoustic waves are generated towards the top of the well; the region constituted by the top surface may be referred to as the bulk acoustic wave action region. The bulk acoustic wave generating area of the UHF acoustic wave resonator is about 15000-²。

The method mainly comprises the following steps:

the bulk acoustic wave resonator devices were fabricated on a 100mm undeposited Si wafer starting with the deposition of bragg reflectors made by alternating PVD and CVD deposited layers of AlN and SiO2, respectively. A sandwich structure comprising a bottom electrode layer (BE), a piezoelectric layer (AlN) and a top electrode layer (TE) is then deposited and patterned layer by layer. Where the bottom electrode layer (BE) is made of 600nm thick Mo and deposited by PVD on top of the bragg reflector, then the film is patterned by photolithography and plasma etching (e.g. into pentagons or triangles) and then PVD deposited piezoelectric layer, which is an AlN film with 1000nm thickness on top of the BE, with 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, with the thickness of the Au electrode and underlying Cr adhesive layer being about 300nm and about 50nm, respectively.The electrode area was configured to be 20,000 μm²So that the resonator has a characteristic impedance of 50T to match the impedance of the external circuit. Polydimethylsiloxane (PDMS) device walls were prepared by soft lithography.

And the power and the time interval of the bulk acoustic wave generated by the ultrahigh frequency resonator are adjusted by a signal generator and a power adjusting device.

Preparation of in vitro rat skin

A healthy SD rat weighing about 200g was anesthetized with pentobarbital, followed by careful subtraction of abdominal hair with a small scissors, shaving with a razor while avoiding skin laceration, peeling the abdominal skin, laying the skin flat on a glass plate with stratum corneum facing down, and wiping off the subcutaneous fat layer and connective tissue with a cotton ball of physiological saline. Washing with normal saline, soaking in normal saline, and taking the product on the same day.

EXAMPLE 2 insulinotropic agent permeable RC-1000 Membrane

30ul of a commercially available insulin injection (300IU/3ml, norathrin 30R, Denmark norathyride) was injected into a liquid supply reservoir connected to the device, capped with an RC-1000 membrane (JMD38, Solarbio), and a receiving reservoir was pressed against the liquid supply reservoir closely across the semipermeable membrane, and 300ul of PBS was injected into the receiving reservoir. The transdermal effect of insulin is measured on the conditions of no power activation of the UHF acoustic wave resonator and power application, which are respectively a control sample and a test sample. Sampling 50ul at 30, 60 and 90 minutes in sequence, wherein the power is 500mW, the frequency is 2.58GHz, the pressure pulse is 0.5S, and the interval is 0.5S. Each set of experiments was repeated 3 times.

The method for measuring the insulin content comprises the following steps: octadecylsilane chemically bonded silica is used as a filler (5-10 μm); taking 0.2mol/L sulfate buffer solution (taking 28.4g of anhydrous sodium sulfate, adding water for dissolution, adding 1.7ml of phosphoric acid, ethanolamine for adjusting the pH value to 2.3, adding water for 1000ml) -acetonitrile (74:26) as a mobile phase; the column temperature was 40 ℃; the detection wavelength was 214 nm. And (3) taking 20 mu L of the system applicability solution (taking an insulin reference substance, adding 0.01mol/L hydrochloric acid solution for dissolving and diluting to prepare a solution containing about 40 units per 1ml, standing for at least 24 hours), injecting into a liquid chromatograph, recording a chromatogram, wherein the separation degree between an insulin peak and an A21 deaminated insulin peak (the relative retention time with the insulin peak is about 1.2) is not less than 1.8, and a tailing factor is not more than 1.8. Precisely measuring 20 mu 1 of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; taking another appropriate amount of insulin reference substance, and measuring by the same method. Calculating according to the sum of the peak area of insulin and the peak area of A21 deaminated insulin by an external standard method to obtain the content.

The results are shown in Table 1, which indicates that the action of the specific acoustic wave promotes the insulin permeation through the regenerated cellulose membrane semipermeable membrane having a cut-off molecular weight of more than 1000.

TABLE 1 results for specific Acceptor membrane permeation into RC-1000

Example 3 insulinotropic hormone permeating rat skin

30ul of a commercially available insulin injection (300IU/3ml, norathrin 30R, Denmark norathyride) was injected into a liquid supply reservoir connected to the device, SD rat excised skin prepared according to the method described in example 1 was capped, a receiving reservoir was pressed against the liquid supply reservoir closely across the rat excised skin, and 300ul of PBS was injected into the receiving reservoir. The effect of dextran on rat skin was measured on control and powered conditions, respectively, in which the bulk acoustic wave resonator was activated without power, and 50ul of dextran was sampled at 30, 60 and 90 minutes, respectively, with power at 500mW, 2.58GHz, 0.5S applied pressure pulse, and 0.5S interval. Each set of experiments was repeated 3 times.

The results of the measurement of insulin content in the same manner as in example 2 are shown in Table 2, which indicates that the action of the specific sound wave promotes the permeation of insulin through the skin of rats.

TABLE 2 results of specific penetration of the skin of SD rats by the acoustic insulinotropic agent

EXAMPLE 4 RC-1000 Membrane-permeable membranes of insulinotropic hydrogels

The insulin hydrogel preparation without transdermal peptide is prepared by referring to the method disclosed in example 1 of Chinese invention patent CN 108653198. The specific method comprises the following steps:

1. the synthesis of unsaturated polyesteramide of arginine (U-Arg-PEA) comprises the following steps:

(1) stirring fumaroyl chloride and p-nitrophenol in acetone containing triethylamine at 0 ℃ for 2 hours, standing overnight at room temperature to obtain a monomer I, and recrystallizing in ethyl acetate for 3 times;

(2) mixing arginine and 1, 4-butanediol, adding the mixture into toluene containing p-toluenesulfonic acid monohydrate, heating to 130 ℃, stirring and refluxing for 24 hours, stirring and dissolving a product in isopropanol at 75 ℃, and precipitating for 3 times at 4 ℃ to obtain a monomer II;

(3) adding the monomer I and the monomer II into dimethyl sulfoxide, uniformly mixing, and dropwise adding triethylamine until the monomers are completely dissolved; stirring at 75 deg.C for 48h, precipitating with ethyl acetate, dissolving in methanol, repeatedly precipitating with ethyl acetate for 3 times, purifying, repeating twice, and vacuum drying to obtain brown yellow solid which is unsaturated polyester amide of arginine (U-ArgPEA).

2. The synthesis of polyethylene glycol diacrylate (PEG-DA) comprises the following steps:

(1) putting polyethylene glycol powder into a round-bottom flask, connecting a device, replacing air with nitrogen, and carrying out ice bath;

(2) adding 30mL of dichloromethane into a round-bottom flask to dissolve polyethylene glycol, adding 0.6mL of triethylamine, adding 20mL of dichloromethane and 2mL of acryloyl chloride into a constant-pressure funnel, mixing the dichloromethane and the acryloyl chloride, adding the mixture into the round-bottom flask at a speed of one drop per second, and stirring at room temperature for 24 hours under the protection of nitrogen;

(3) precipitating with 400mL of glacial ethyl ether, carrying out suction filtration, and then carrying out vacuum drying to obtain white powder, namely the polyethylene glycol diacrylate.

3. A method of making a hydrogel comprising the steps of:

(1) uniformly dispersing unsaturated polyesteramide of arginine and polyethylene glycol diacrylate in a mass ratio of 1:1 into water to enable the sum of the mass percentages of the unsaturated polyesteramide and the polyethylene glycol diacrylate to be 15%, and adding a proper amount of insulin to enable the sum of the mass percentages of the insulin photoinitiator and the water to be 85%;

(2) adding 1% of photoinitiator I2959, mixing well, injecting into a mould, and processing with intensity of 100mW/cm²The hydrogel was irradiated with ultraviolet light for 100 seconds to obtain a hydrogel (Gel 2: PEG-DA/U-Arg-PEA/Insulin/TD-1).

And taking the prepared insulin hydrogel preparation, and cutting the insulin hydrogel preparation to the size corresponding to the ultrahigh frequency bulk acoustic wave resonator device. The cut insulin hydrogel preparation is attached to the surface of the UHF bulk acoustic resonator, the drug release surface is attached to an RC-1000 membrane (JMD38, Solarbio), the other surface of the membrane is tightly contacted with a receiving pool, and 300ul PBS is injected into the receiving pool. The transdermal effect of insulin is measured on the conditions of no power activation of the UHF acoustic wave resonator and power application, which are respectively a control sample and a test sample. The power was 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Samples were taken at 30, 60 and 90 minutes respectively to determine the transdermal efficiency of insulin. Each set of experiments was repeated 3 times. The results of the same insulin content measurement method as in example 2 are shown in table 3, which indicates that the membrane permeation of the insulin hydrogel preparation can be significantly improved by the action of the specific sound wave.

TABLE 3 results of specific penetration of the membrane RC-1000 by the insulinotropic agent

Example 5 insulinotropic hydrogel rat skin

The insulin hydrogel formulation prepared in example 4 was taken and cut to a size corresponding to the uhf bulk acoustic wave resonator device. The cut insulin hydrogel preparation is attached to the surface of the ultrahigh frequency bulk acoustic wave resonator, the drug release surface is sealed with the abdominal skin of a rat, the other surface of the rat skin is tightly contacted with a receiving pool, and 300ul PBS is injected into the collecting pool. The transdermal effect of insulin was measured under conditions of no power and power, respectively, as control and test samples, respectively. The power was 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. Samples were taken at 30, 60 and 90 minutes respectively to determine the transdermal efficiency of insulin. Each set of experiments was repeated 3 times. The method for measuring the insulin content was the same as in example 2. The results are shown in table 4, which indicates that the specific acoustic wave effect significantly improves the rat skin penetration effect of the insulin hydrogel formulation.

TABLE 4 results of specific penetration of the skin of rats by the acoustic insulinotropic hormone

Example 6 evaluation of transdermal drug efficacy of insulinotropic hormone in rats

Male rats weighing approximately 200g SD were taken free to drink and eat water and bedding was changed daily. Before the start of the experiment, all rats were subjected to the study conditions for 3 days of acclimation, labeled and weighed, and the dose of STZ required for diabetes modelling per rat was calculated from the 45mg/kg dose. 100mg of STZ (streptozotocin) was dissolved in a citrate buffer (pH 4.0, membrane-sterilized) and the corresponding dose of STZ solution was injected into the tail vein according to the body weight of different SD rats. After 4 days, all rats are subjected to intravenous injection to test blood sugar, and the average blood sugar is more than 16.7mmol/L, which indicates that the diabetes molding is successful.

A commercially available insulin injection (300IU/3ml, norathrin 30R, Denmark norathyride) 300ul was injected into the fluid reservoir, which was tightly sealed with an RC-1000 membrane (JMD38, Solarbio), and the fluid reservoir was fixed to the abdomen of the rat anesthetized with ether, and one side of the RC-1000 membrane of the fluid reservoir was in contact with the abdomen. The transdermal effect of the insulin is measured on the condition that the ultrahigh frequency acoustic wave resonator is activated without power to generate bulk acoustic waves and the condition that the ultrahigh frequency acoustic wave resonator is activated with power are respectively used as a control sample and a test sample. The power is 500mW, 2.58GHz, 0.5S pressure pulse, 0.5S interval, release for 90 minutes. The change of blood sugar is detected at 2, 4, 6, 8, 10 and 12 hours, compared with the synchronous blood sugar of a normal anesthesia non-drug administration group, and an insulin group with the same amount of intravenous injection is additionally arranged to be used as a positive control. Each set of experiments was repeated 3 times. The results are shown in Table 5. TABLE 5 results of in vivo experiments on the skin penetration of specific insulinotropic agents in rats

Experiments show that under the same conditions, compared with a control group without power, the power-added group can obviously reduce the blood sugar content in the animal body, which indicates that the transdermal effect is obvious; compared with intravenous injection administration group, the power group has the effect of sustained drug release, and can maintain the remarkable blood sugar reducing effect within 8 hours, and the intravenous injection administration group can lose the effective blood sugar reducing effect after 2 hours to achieve the maximum blood sugar reducing effect and 4 hours later. The blood sugar reducing effect of the special acoustic wave transdermal device has the characteristics of high efficiency and long effect, and has obvious advantages compared with the prior art.

Example 7 transdermal drug efficacy evaluation of insulinotropic hydrogel in rats

Referring to the animal experiment of example 22, the insulin hydrogel formulation prepared in example 4 was cut to a size corresponding to that of the uhf bulk acoustic wave resonator device. And (3) attaching the cut insulin hydrogel preparation to the surface of the ultrahigh frequency bulk acoustic wave resonator to form the insulin medicament hydrogel transdermal patch. The transdermal effect of the insulin is measured by attaching the transdermal agent to the abdomen of a rat anesthetized by ether under the condition of not adding power to activate an ultrahigh frequency acoustic wave resonator to generate a bulk acoustic wave and adding power respectively, and the transdermal effect is taken as a control sample and a test sample respectively. The power conditions were 500mW, 2.58GHz, 0.5S pressure pulse, 0.5S interval. Release the drug for 90 minutes. The change of blood sugar is detected at 2, 4, 6, 8, 10 and 12 hours, compared with the synchronous blood sugar of a normal anesthesia non-drug administration group, and an insulin group with the same amount of intravenous injection is additionally arranged to be used as a positive control. Each set of experiments was repeated 3 times. The insulin content was measured in the same manner as in example 2, and the results are shown in Table 6.

TABLE 6 results of in vivo experiments of the specific acoustic insulinotropic hydrogel formulation through rat skin

Experiments show that under the same conditions, compared with a control group without power, the power-added group can obviously reduce the blood sugar content in the animal body, which indicates that the transdermal effect is obvious; compared with intravenous injection administration group, the power group has the effect of sustained drug release, and can maintain the remarkable blood sugar reducing effect within 10 hours, and the intravenous injection administration group can lose the effective blood sugar reducing effect after 2 hours to achieve the maximum blood sugar reducing effect and 4 hours later. Therefore, the blood sugar reducing effect of the special sound wave transdermal preparation has the characteristics of high efficiency and long acting, and has obvious advantages compared with the prior art.

Example 8 RC-1000 Membrane permeants of flurbiprofen hydrogel

A commercially available hydrogel preparation flurbiprofen babu paste (Beijing Taide pharmacy) is cut to the size corresponding to the ultrahigh frequency bulk acoustic resonator device. The cut flurbiprofen cataplasm backing is attached to the surface of the ultra-high frequency bulk acoustic resonator, the drug release surface is attached to an RC-1000 film (JMD38, Solarbio), the other surface of the film is tightly contacted with a receiving pool, and 300ul of PBS is injected into the receiving pool. The transdermal effect of insulin is measured on the conditions of no power activation of the UHF acoustic wave resonator and power application, which are respectively a control sample and a test sample. The power was 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. The transdermal efficacy of flurbiprofen was determined by sampling at 30, 60, 90 and 120 minutes respectively.

The method for detecting flurbiprofen is as follows: taking the product, precisely weighing, dissolving in solvent [ acetonitrile-water (45:55) ] and diluting to obtain solution containing 2.0mg per 1ml as control solution, and sampling at different times to obtain test sample. Octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-water-glacial acetic acid (35:60:5) is used as a mobile phase; the detection wavelength was 254 nm. Precisely measuring 20 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times. Calculated as peak area by external standard method.

The results are shown in table 7, which indicate that the effect of the terbutaline can significantly improve the membrane permeation effect of the flurbiprofen hydrogel formulation.

TABLE 7 results of permeation of RC-1000 membrane by Teflon-promoted flurbiprofen hydrogel

Example 9 transdermal rat skin of flurbiprofen hydrogel

A commercially available hydrogel preparation flurbiprofen babu paste (Beijing Taide pharmaceutical) is cut to a size corresponding to that of a Techonic wave excitation device. The cut flurbiprofen cataplasm backing is attached to the surface of the ultra-high frequency bulk acoustic resonator, the drug release surface is sealed with the abdominal skin of a rat, the other surface of the rat skin is tightly contacted with a receiving pool, and 300ul PBS is injected into the collecting pool. The transdermal effect of flurbiprofen was measured without and with power, respectively, as control and test samples. The power was 500mW, frequency 2.58GHz, 0.5S pressure pulse, 0.5S interval. The transdermal efficacy of flurbiprofen was determined by sampling at 30, 60, 90 and 120 minutes respectively. The method for detecting flurbiprofen was the same as in example 8.

The measurement results are shown in table 8, which indicates that the effect of the tesonic wave can significantly improve the transmembrane effect of the flurbiprofen hydrogel preparation.

TABLE 8 results of the permeation of the terbufloxoprofen hydrogel through rat skin

Although exemplary embodiments of the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. For other examples, one of ordinary skill in the art will readily appreciate that the order of the process steps may be varied while maintaining the scope of the present invention.

Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed, that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.

Claims

1. A method of administering a biologically active agent to a patient via transdermal delivery, the method comprising:

(1) providing a reservoir containing a biologically active agent, such as small molecule compounds, polypeptides, proteins such as insulin, oligonucleotides, nucleic acids, and polysaccharides, for holding a solution, suspension, or gel containing the active agent,

(2) activating one or more ultra-high frequency acoustic wave resonators (e.g., thin film bulk acoustic resonators or solid assembly resonators) to generate bulk acoustic waves in the solution, suspension or gel at a frequency of about 0.5-50GHz, such that the bioactive agent enters or permeates the skin of the patient,

preferably, the power of the bulk acoustic wave generated by the UHF acoustic wave resonator is about 0.1-50W, preferably 0.2-10W, more preferably 0.5-5W,

preferably, wherein the bulk acoustic wave generating region area of the UHF acoustic wave resonator is about 1000-50000 mu m²Preferably about 5000-²。

2. The method of claim 1, wherein the reservoir contains a gel, preferably a hydrogel.

3. The method of claim 2, wherein the gel is in contact with the skin of the patient or is in contact with the skin of the patient through a semi-permeable membrane.

4. The method of claim 1, wherein the bioactive agent has a molecular weight of 200 to 1000000 daltons.

5. The method of claim 1, wherein the uhf acoustic resonator is at a distance of about 0.1-20mm, preferably 0.5-15mm, most preferably about 1-10mm from the patient's skin.

6. A device for transdermal delivery of an active agent to a patient comprising

Gels containing active agents (e.g., hydrogels); for example, wherein the active agent is a small molecule compound, polypeptide, protein such as insulin, oligonucleotide, nucleic acid, and polysaccharide;

one or more ultra-high frequency bulk acoustic resonators (e.g., thin film bulk acoustic resonators or solid state fabricated resonators) in contact with the bottom of the gel, the one or more ultra-high frequency bulk acoustic resonators being configured to generate bulk acoustic waves in the gel at a frequency of about 0.5-50GHz,

preferably, wherein the upper surface of the gel has a semi-permeable membrane.

7. The device of claim 6, wherein the gel has a thickness of about 0.1-20mm, preferably 0.5-15mm, most preferably about 1-10 mm.

8. A transdermal drug delivery formulation comprising:

an active agent-containing gel (preferably a hydrogel); such as small molecule compounds, polypeptides, proteins such as insulin, oligonucleotides, nucleic acids, and polysaccharides; wherein the thickness of the gel is, for example, about 0.1 to 20mm, preferably 0.5 to 15mm, most preferably about 1 to 10 mm;

one or more removable bulk acoustic wave resonators (e.g., film bulk acoustic resonators or solid-state fabricated resonators) in contact with the bottom of the gel, the one or more bulk acoustic wave resonators being configured to generate bulk acoustic waves in the gel at a frequency of about 0.5-50GHz,

preferably, wherein the upper surface of the gel has a semi-permeable membrane.

9. The pharmaceutical formulation of claim 8, wherein the upper surface of the gel 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-adherent polymers.

10. The pharmaceutical formulation of claim 8, wherein the gel has a support layer on the bottom, preferably the uhf resonator is removably mounted to the support layer.