CN112057738B - Transdermal drug delivery methods and devices - Google Patents
Transdermal drug delivery methods and devices Download PDFInfo
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- CN112057738B CN112057738B CN202010520121.4A CN202010520121A CN112057738B CN 112057738 B CN112057738 B CN 112057738B CN 202010520121 A CN202010520121 A CN 202010520121A CN 112057738 B CN112057738 B CN 112057738B
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- 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
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
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- 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
- A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
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Abstract
本发明提供了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。
The present invention provides a method and device for promoting transdermal release of drugs by using an ultra-high frequency resonator to generate bulk acoustic waves. The method of the present invention can achieve transdermal release of substances that are difficult or impossible to penetrate the skin, including but not limited to small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and other biologically active substances.
Description
The present application claims priority from chinese patent application No. 201910496314.8, entitled "transdermal delivery method and device," filed on 6/10/2019, the entire contents of which are incorporated herein by reference.
Technical Field
The present invention relates to a method and apparatus for drug delivery. More particularly, the present invention relates to methods and apparatus for using ultra-high frequency resonators to generate bulk acoustic waves to facilitate transdermal drug delivery. The method of the present invention can achieve transdermal penetration of materials that are not easily or transdermally permeable, including but not limited to small molecule chemicals, polypeptide drugs, and bioactive materials such as antibodies and vaccines.
Background
The skin is covered on the surface layer of the human body and is directly contacted with the external environment, so that the external matters 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. Wherein the epidermis is composed of a multi-layer flat epithelium, and comprises a cuticle, a transparent layer, a granular layer and a hair growing layer from shallow to deep. The stratum corneum is composed of multiple layers of keratinocyte epithelial cells (nucleus and organelle disappear, cell membranes are thicker) and intercellular lipids, is inanimate and waterproof, has the functions of preventing tissue fluid outflow, resisting friction, preventing infection and the like, and is a main barrier for exogenous substances to be absorbed through skin. The dermis is composed of compact connective tissue, and comprises a nipple layer and a reticular layer from shallow to deep in sequence, wherein the reticular layer is connected with subcutaneous tissue, and is provided with abundant collagen fibers, elastic fibers and reticular fibers which are mutually interwoven into a net, so that the skin has higher 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 local tissues or the systemic circulatory system without substantial cutting or puncturing of the skin, such as cutting with a surgical knife or puncturing of the skin with a hypodermic needle. The transdermal drug delivery system has the advantages of no influence of pH, food, transport time and other factors in digestive tract, avoiding liver first pass effect, overcoming untoward effect caused by too high blood concentration caused by too fast absorption, continuously controlling the drug delivery speed, flexibly delivering drug and the like.
In the dermal drug delivery system, the epidermis, and particularly the stratum corneum, is the primary barrier for drug entry into the body, and studies have found that only a very small number of drugs have excellent skin permeability, and that most drugs do not readily cross the skin of the human body as an effective, selective barrier. The epidermis, and in particular the stratum corneum, is the primary barrier layer, and once its protective function is lost, a large number of water-soluble, non-electrolyte molecules diffuse into the systemic circulation at thousands of times faster, so that promotion of transdermal absorption of the drug is primarily a reduction of the barrier of this barrier layer.
The prior technology for dynamically opening the compact structure of the stratum corneum to realize transdermal drug delivery mainly comprises chemical permeation promotion, physical permeation promotion (electric conduction, micro-needle) and the like. Chemical permeation is achieved mainly by a substance which can reversibly change the barrier function of the stratum corneum of the skin without damaging any active cells, enhance the transdermal capacity of the drug, and increase the transdermal amount of the drug. The advantage of chemical permeation promotion is that the chemical permeation promotion can be integrated with a pharmaceutical preparation, but skin red swelling, pain and other stimulations can be generated when the dosage is large or the dosage is long, and the compatibility with pharmaceutical ingredients is also an important factor for limiting the application of the chemical permeation promotion.
Common single physical technique infiltration promotion methods are microneedles, electrets, ions, electroporation, laser, magnetic field introduction, thermal perforation. The micro-needle permeation promotion is to stick a transdermal patch consisting of tens to hundreds of hollow or solid micro-needles to the skin, penetrate through the stratum corneum barrier and manufacture micro-channels in the epidermis layer, and the medicine enters the systemic circulation through the micro-channels, so that the medicine can be promoted to permeate into specific parts through the skin, and the micro-needle permeation promotion method is suitable for macromolecular medicines (such as polypeptides, proteins, vaccines and the like with lower skin permeability). The electroporation technique is a method for improving permeability of cell and tissue membranes by changing directional arrangement of lipid molecules in skin stratum corneum under the action of instant high-voltage pulse current and increasing disordered structure of lipid bilayer to form transient and reversible hydrophilic pore canal, and is suitable for small molecule drugs (such as insulin) with good ionization performance, but has limited popularization due to the dependence of a charged device and the characteristics of energy. The laser technology is a physical permeation promotion technology which utilizes the impact of the laser to the skin by the optical mechanical wave formed by the impact of the laser to the target substance, and the generated energy erodes or erodes the stratum corneum, changes the molecular arrangement of organism tissues and forms dense pore channels, thereby promoting the percutaneous absorption of macromolecular medicaments. Magnetic field introduction and permeation promotion are physical techniques for improving the percutaneous permeability of drugs by applying a magnetic field. The thermal perforation technique is a technique for forming hydrophilic channels in the stratum corneum by pulse heating to increase skin permeability. Although the magnetic field introduction and thermal perforation technology can improve the percutaneous transmittance of the medicine, the complexity and high cost of manufacturing are the difficult problems to be broken through.
The specific mechanism of action of the method for introducing drugs by ultrasound has been reported, but has not yet been fully elucidated, and cavitation is considered to be the most dominant mechanism of action of ultrasound penetration by the mainstream view. Cavitation refers to the process of ultrasonic wave propagation in a medium, gas cavitation formation, expansion, contraction and disintegration. The current results indicate that the lower the frequency, the better the cavitation effect [ Hideo U.S. et al, pharmacy Bullet,2009,32 (32); 916-920 ], so the use of low frequency (especially 20 KHz) ultrasound and the use of some surface active substances to reduce the surface tension of the liquid medium is the primary direction of research to increase cavitation effect and increase drug permeability.
The ultra-sound wave refers to ultra-high frequency longitudinal sound wave with the frequency exceeding 0.3GHz, and is mainly used in the communication field, and the ultra-high frequency sound wave is never applied to the biological penetration promotion application because the penetration promotion effect of low-frequency ultrasonic waves is well known in the prior art. Research by Duan Xuexin et al in 2017 found that ultra-high frequency ultra-sonic waves (1.6 GHz, 300 mW) can form nanopores in the cell membrane instantaneously, so that drug molecules, DNA fragments and gene lipid particles penetrate through the cell membrane to enter cytoplasm [ Duan Xuexin, etc., small 2017,1602962 ]. Further research results show that the liposome can be used for carrying and releasing medicine of double-layer lipid membranes and liposomes [ section science euphoria and the like ], angew.chem.int.ed.10.1002/anie.201810181 ]. However, the published literature is limited to the effect on cell membranes or cell membrane-like bilayer liposomes, but the stratum corneum which limits the transdermal effect is composed of multiple layers of keratinocytes (nuclear and organelle disappearing, thicker cell membranes) and intercellular lipids closely packed, is inanimate and waterproof, has great differences in composition, density and thickness with the structure of the cell membranes, and therefore cannot judge the possibility and safety of the technology applied to physical transdermal promotion.
There is also a need in the art for methods and devices for transdermal delivery that are effective and safe.
Disclosure of Invention
The present invention provides a new method and apparatus for transdermal delivery of biologically active substances, particularly drug molecules that are not readily or transdermally permeable, using a ultra-high frequency resonator to generate bulk acoustic waves. The method provided by the invention can effectively and safely deliver biological drugs such as small molecule chemical drugs, polypeptide drugs, antibodies, vaccines and the like.
In particular, the present invention provides a method of administering a bioactive agent to a patient by transdermal delivery, the method comprising:
(1) Providing a reservoir (reservoir) containing a bioactive agent, the reservoir for containing a solution, suspension or gel containing the bioactive agent,
(2) One or more ultra-high frequency acoustic wave resonators are activated to generate bulk acoustic waves in the solution, suspension or gel at a frequency of about 0.5-50GHz so that the bioactive agent enters or penetrates the patient's skin.
The term "transdermal" as used herein refers to delivery of a drug into and/or through the skin for local or systemic therapeutic purposes.
Patient refers to humans or other animals including, but not limited to, other primates such as chimpanzees and other apes and monkeys, farm animals such as cattle, sheep, pigs, goats and horses, domestic animals such as dogs and cats, laboratory animals including rodents such as mice, rats and guinea pigs, birds including domestic, wild and playing birds such as chickens, turkeys and other galliformes, ducks, geese, and the like.
Bioactive agent refers to a composition of matter or mixture containing an active agent or drug that is pharmacologically effective when administered to a patient in a therapeutically effective amount. Examples of bioactive agents include, but are not limited to, small molecular weight compounds, polypeptides, proteins, oligonucleotides, nucleic acids, and polysaccharides.
In the method of the present invention, the molecular weight of the bioactive agent ranges from 200 to 1000000 daltons.
In the methods of the invention, the bioactive agent may also be delivered by attachment to a carrier. The carrier may be any solid substrate used in biotechnology for immobilization. Such a carrier may be a particle, a sheet, a membrane, a gel, a filter, a microtiter belt, 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, goserelin and napfarelin, urotropin (FSH) and LH)); vasopressin; desmopressin, adrenocorticotropic hormone (ACTH), ACTH analogs such as ACTH (1-24), calcitonin, vasopressin, deamino [ Val4, D-Arg8] arginine vasopressin, interferon alpha, interferon beta, interferon gamma, erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), glucagon, ghRF (GHRF), insulin, insulinotropic hormone, calcitonin, octreotide, TRN, NT-36 (chemical name: N- [ [ [ (S) -4-oxo-2-azetidinyl ] carbonyl ] -L-histidinyl-L-prolinamide), liprecin, alpha ANF, beta MSH, somatostatin, bradykinin, growth hormone, platelet derived growth factor release factor, chymopapain, chymosin, gonadotropin, epothilone, prostanol (platelet aggregation inhibitor), glucagon, heme-K, L-N-C-L, L Enzymes, ANP clearance inhibitors, BNP, VEGF, angiotensin II antagonists, anti-diuretic agonists, bradykinin antagonists, ceredase, CSI' S, calcitonin Gene Related Peptide (CGRP), enkephalin, FAB fragments, igE peptide inhibitors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentetate, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vasopressin antagonist analogs, alpha-1 antitrypsin (recombinants), TGF-beta, fondaparinux, adapal, defibrinoheparin, hirudin, nadroparin, heparin, tinzaparin, pentosan polysulfate, oligonucleotides and oligonucleotide derivatives such as formivirsen, alendronic acid, etidronic acid, ibandronic acid, pranoproflumic acid, and norvalinate, rwbane 35, and alfa-35.
The methods of the invention are particularly suitable for use with pharmaceutically active agents that are not readily or transdermally permeable. For example, a larger volume of active agent such as a polypeptide or protein. Proteins may include, among others, cytokines, hormones, vitamins, surface receptors, haptens, antigens, antibodies, enzymes, growth factors, recombinant proteins, toxins, and fragments and combinations thereof. In addition, there are various small molecule drugs in the art which are unsuitable or impossible to pass through a conventional transdermal preparation due to physical properties such as hydrophobicity.
In one aspect of the invention, the active agent is present in a solution or suspension. In yet another aspect of the invention, the solution or suspension is contacted with the skin of the patient. In another of its aspects, the solution or suspension is contacted with the patient's skin through a semipermeable membrane. The solution or suspension may be added directly to the reservoir of the device of the present invention to encapsulate the upper surface of the reservoir with a semipermeable membrane. The solution or suspension may also be provided in a pre-packaged form. The encapsulated material includes a semipermeable membrane.
In the methods of the invention, the solution or suspension is a solvent in which the various bioactive agents are soluble. In one aspect of the invention, the solvent contained in the solution or suspension is an aqueous solvent, such as water. In another aspect of the invention, the solution may also include a non-aqueous solvent such as ethanol, chloroform, ether, propylene glycol, polyethylene glycol, and the like. In the methods of the invention, the solutions, suspensions may contain inert fillers, permeation enhancers, excipients, and other conventional components of transdermal devices known in the art, in addition to the bioactive agent.
In the method of the present invention, the semipermeable membrane is a semipermeable membrane through which the active agent cannot freely diffuse. Semipermeable membranes useful in the methods of the present invention refer to a variety of natural and artificial membranes known in the art that have selective retention of compounds of different molecular weight sizes, 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.
In the method of the invention, the bioactive agent may be present in the solution, suspension in any possible amount. Suitable amounts may be found by reference to transdermal formulations known in the art, or by testing by known methods. For example, since the method of the present invention can adjust the amount of transdermal active agent by controlling various parameters of the ultra-high frequency acoustic resonator for generating acoustic waves, the appropriate amount in solution, suspension can be experimentally detected and selected to ensure that the active agent is administered to the patient in a therapeutically effective and safe amount.
In the methods of the invention, a depot containing a bioactive agent (reservoir) is employed. The reservoir is adapted to hold a solution, suspension or gel. The solution or suspension of the active agent may be added directly to the reservoir and then encapsulated by the semipermeable membrane on the upper surface of the reservoir, or may be provided in a pre-packaged form. The material of the encapsulation may be a semipermeable membrane or the like. For example, the reservoir has four rims for holding solutions or suspensions or gels. For another example, the reservoir has two to four rims or detents for holding a packaging bag of solution or suspension.
In the method of the present invention, ultra-high frequency (about 0.5-50 GHz) bulk acoustic waves are generated in solution using an ultra-high frequency acoustic wave resonator. Particles (e.g., bioactive agents) in the ultra-high frequency formed bulk acoustic wave region are subjected to a fluid drag force (Stokes drag force), the inertial drag force (INERTIAL LIFT force) created by laminar flow, and the acoustic radiation force (acoustic radiation force) caused by acoustic attenuation. Under suitable conditions (nature of the solution and particles, intensity of the bulk acoustic wave, distance the particles travel, etc.), the bulk acoustic wave induces a flow of particles in the solution in the direction of acoustic wave propagation, is able to pass through the skin into the interior of the skin, and does not cause irreversible damage to the skin.
The ultra-high frequency acoustic wave resonator adopted by the invention can generate ultra-high frequency (about 0.5-50 GHz) vibration, and bulk acoustic waves with corresponding frequencies are induced in the solution. In one aspect of the present invention, the ultra-high frequency acoustic wave resonator is a film bulk acoustic wave resonator (FBAR) or a solid state fabricated resonator (SMR), preferably a solid state fabricated resonator. In still another aspect of the present invention, the ultra-high frequency acoustic resonator is an acoustic resonator of a thickness extensional vibration mode, and the piezoelectric material thin film layer is grown in a vertical direction, and the vibration is excited by coupling a vertical electric field through a d33 piezoelectric coefficient. The ultra-high 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. And the overlapping area of the bottom electrode layer, the piezoelectric layer, the top electrode layer and the sound wave reflecting layer forms a bulk sound wave generating area. The top surface of the ultra-high frequency acoustic wave resonator is arranged on a wall (such as the bottom of a reservoir of the present invention) of a container for containing liquid, and a bulk acoustic wave having a propagation direction perpendicular to the wall is generated to the opposite wall, and a region constituted by the top surface may be referred to as a bulk acoustic wave action region. The thickness of the piezoelectric layer of the ultra-high frequency acoustic wave resonator is about 1 nm-2 um. The ultra-high frequency acoustic wave resonator of the present invention has a frequency of about 0.5 to 50GHz, preferably about 1 to 10GHz.
In the present invention, the shape of the acoustic wave action region may be any shape. In one aspect of the invention, the bulk acoustic wave generating region of the ultra-high frequency acoustic wave resonator has a width of about 50-300 μm, for example about 70-150 μm. In still another aspect of the present invention, the volume acoustic wave generating region of the ultra-high frequency acoustic wave resonator has an area of about 1000 to 50000 μm 2, preferably about 5000 to 20000 μm 2.
In one aspect of the invention, in the method of delivering a bioactive agent to a patient by transdermal delivery, the ultra-high frequency acoustic wave resonator is spaced from the skin of the patient by a distance of about 0.1 to 20mm, preferably 0.5 to 15mm, and most preferably about 1 to 10mm.
The inventors of the present application have unexpectedly found that when the distance between the ultra-high frequency acoustic wave resonator and the skin of the patient is about 0.1 to 20mm, the active agent can be effectively transmitted through the skin, and at the same time, the activity of biomolecules such as proteins can be maintained, and the transdermal efficiency is high. In yet another aspect of the application, the height of the reservoir is about 0.1-20mm, preferably 0.5-15mm, most preferably about 1-10mm. The upper surface of the reservoir is in contact with the patient's skin during administration, so that the height of the reservoir corresponds to the distance of the ultra-high frequency acoustic resonator from the patient's skin.
In one aspect of the invention, the transdermal efficiency of the bioactive agent can be modulated 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 conditioning 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 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, saw tooth wave, or triangular wave. The pulsed voltage signal may also have amplitude or frequency modulation 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 by transdermal delivery is also provided. The device comprises:
A reservoir containing an active agent, the reservoir being for containing a solution or suspension containing an active agent;
One or more ultra-high frequency bulk acoustic wave resonators disposed at the bottom of the reservoir, the one or more ultra-high frequency bulk acoustic wave resonators generating bulk acoustic waves in the solution or suspension having a frequency of about 0.5-50 GHz. The solution or suspension containing the active agent is contacted with the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are disposed at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonator is arranged such that the propagation direction of bulk acoustic waves generated in said solution or suspension is towards the top of the reservoir, i.e. the surface in contact with the patient's skin.
In one aspect of the invention, the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot freely diffuse. In one aspect of the invention, the outer surface of the semipermeable membrane may also have a peelable sealing membrane that peels off prior to use (contact with the patient's skin).
In one aspect of the invention, the reservoir has an opening or aperture adapted for the addition of a solution or suspension, or for loading a pouch containing a solution or suspension.
In one aspect of the invention, the device further comprises a housing, and the reservoir is removably coupled to the housing. The housing has a mechanism, such as a buckle strap or the like, adapted to be secured to a human or animal body such that the upper surface of the reservoir 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 high frequency signal generator and an interface provided on the device housing. For another example, the uhf resonator has a circuit that receives a radio frequency signal. When the active agent is to be administered for a prolonged period of time or for timed administration, the device further comprises a timed emission signal system to excite the ultra-high frequency bulk acoustic resonator for a specified period of time or 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 resonator in the device is a thin film bulk acoustic resonator or a solid state assembly resonator, such as a thickness extensional vibration mode acoustic resonator.
In one aspect of the invention, the height of the reservoir (bottom to top, such as distance to the semipermeable membrane at the top) is about 0.1-20mm, preferably 0.5-15mm, and most preferably about 1-10mm. The upper surface of the reservoir is in contact with the patient's skin during administration, so that the height of the reservoir corresponds to the distance of the uhf acoustic resonator arranged at the bottom of the reservoir from the patient's skin.
In one aspect of the invention, the bulk acoustic wave generation region area of the ultra-high frequency acoustic wave resonator in the device is about 1000-50000 μm 2, preferably about 5000-20000 μm 2.
In one aspect of the invention, the ultra-high frequency acoustic wave resonator in the device generates a bulk acoustic wave having a power of about 0.1 to 50W, preferably 0.2 to 10W, and more preferably 0.5 to 5W.
In one aspect of the present invention, there is also provided a transdermal drug delivery composition comprising:
a reservoir containing a solution or suspension containing an active agent;
One or more ultra-high frequency bulk acoustic wave resonators removably disposed at the bottom of the reservoir, the one or more ultra-high frequency bulk acoustic wave resonators generating bulk acoustic waves having a frequency of about 0.5-50GHz in the solution or suspension. The solution or suspension containing the active agent is contacted with the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are disposed at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonator is arranged such that the propagation direction of bulk acoustic waves generated in said solution or suspension is towards the top of the reservoir, i.e. the surface in contact with the patient's skin.
In one aspect of the invention, the upper surface of the reservoir has a semipermeable membrane through which the active agent cannot freely diffuse. In one aspect of the invention, the outer surface of the semipermeable membrane may also have a peelable sealing membrane that peels off prior to use (contact with the patient's skin).
In one aspect of the invention, the reservoir has an opening or aperture adapted for the addition of a solution or suspension, or for loading a pouch containing a solution or suspension.
In one aspect of the invention, the uhf resonator in the composition has a circuit that receives a pulsed voltage signal. For example, the uhf resonator has a circuit for receiving a connection to an external high frequency signal generator and an interface provided on the device housing. For another example, the uhf resonator has a circuit that receives a radio frequency signal. When the active agent is to be administered for a prolonged period of time or for timed administration, the device further comprises a timed emission signal system to excite the ultra-high frequency bulk acoustic resonator for a specified period of time or 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 resonator in the composition is a thin film bulk acoustic resonator or a solid state assembly resonator, such as an acoustic resonator of thickness extensional vibration mode.
In one aspect of the invention, the height of the reservoir in the composition (bottom to top, e.g., distance to the semipermeable membrane at the top) is about 0.1-20mm, preferably 0.5-15mm, and most preferably about 1-10mm. The upper surface of the reservoir is in contact with the patient's skin during administration, so that the height of the reservoir corresponds to the distance of the uhf acoustic resonator arranged at the bottom of the reservoir from the patient's skin.
In one aspect of the invention, the ultra-high frequency acoustic wave resonator in the composition has a bulk acoustic wave generating area of about 1000-50000 μm 2, preferably about 5000-20000 μm 2.
In one aspect of the invention, the ultra-high frequency acoustic wave resonator in the composition generates a bulk acoustic wave having a power of about 0.1 to 50W, preferably 0.2 to 10W, and more preferably 0.5 to 5W.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 shows an exemplary experimental setup diagram of the present invention.
Fig. 2 illustrates an exemplary ultra-high frequency acoustic wave resonator of the present invention.
Fig. 3 shows a schematic diagram of an exemplary embodiment of a transdermal delivery composition of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments of the present invention. All other embodiments, which can be made by one of ordinary skill in the art without undue burden on the person of ordinary skill in the art based on embodiments of the present invention, are intended to be within the scope of the present invention.
Example 1 Experimental apparatus and Material preparation
The experimental setup was set up as shown in fig. 1. Including two height-adjustable wells surrounded by Polydimethylsiloxane (PDMS) material walls. The well below is connected with the circuit board with the ultra-high frequency acoustic wave resonator in a sealing way to form a liquid supply tank capable of containing liquid or gel. In the experiment, the volume of the liquid supply tank was adjusted to about 30. Mu.L and the height was adjusted to about 1mm. The top of the liquid supply tank is covered by a semipermeable membrane and/or mouse skin. A solution or gel containing the active substance is added to the liquid supply reservoir. The resonator may generate bulk acoustic waves in the liquid in the chamber at a frequency of about 0.5-50GHz toward the top. According to different experiments, the upper well and the liquid supply tank are separated by a semipermeable membrane and/or animal skin samples, and the upper well can be added with a solution such as PBS (phosphate buffered saline) for receiving the active substances permeated from the liquid supply tank, and the solution is also called a receiving tank.
Fig. 2 is a physical photograph of an exemplary ultra-high frequency acoustic wave resonator, i.e., a photoacoustic wave, of the method and apparatus of the present invention, which generates a bulk acoustic wave having an area of about 15000-20000 μm 2. The left diagram of fig. 2 shows the ratio of the uhf acoustic wave resonator device to the coin. The right diagram of fig. 2 shows the area and pattern of the ultra-high frequency acoustic wave resonator for generating the bulk acoustic wave (the pattern illustrated in the figure is pentagonal).
Fig. 3 is a schematic view of a transdermal delivery composition provided by the present invention.
Wherein the transdermal drug delivery composition comprises a reservoir 10 containing an active agent, the reservoir being configured to contain a solution or suspension 20 containing an active agent, and a plurality of ultra-high frequency bulk acoustic wave resonators 30 disposed at the bottom of the reservoir, the one or more ultra-high frequency bulk acoustic wave resonators generating bulk acoustic waves having a frequency of about 0.5-50GHz in the solution or suspension. The solution or suspension containing the active agent is contacted with the patient's skin through the top of the reservoir. The one or more ultra-high frequency bulk acoustic wave resonators are disposed at the bottom of the reservoir. The ultra-high frequency bulk acoustic wave resonator is arranged such that the propagation direction of bulk acoustic waves generated in said solution or suspension is towards the top of the reservoir, i.e. 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 freely diffuse.
Preparing an ultrahigh frequency acoustic wave resonator:
The ultra-high frequency acoustic wave resonator was prepared according to the reported method (Zhixin Zhang et al, small 2017,13,1602962-1602980). The ultrahigh frequency acoustic 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. And the overlapping area of the bottom electrode layer, the piezoelectric layer, the top electrode layer and the sound wave reflecting layer forms a bulk sound wave generating area. The top surface of the ultra-high frequency acoustic wave resonator is arranged at the bottom of the PDMS well, and generates bulk acoustic waves to the top of the well, and the area formed by the top surface can be called a bulk acoustic wave action area. The volume sound wave generation area of the ultra-high frequency sound wave resonator is about 15000-20000 mu m 2.
The method mainly comprises the following steps:
Bulk acoustic wave resonator devices were fabricated on 100mm undeposited Si wafers, starting with the deposition of bragg reflectors, which were made by alternating deposition of AlN and SiO2 layers by PVD and CVD, 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. Wherein the bottom electrode layer (BE) is made of Mo 600nm thick and deposited by PVD on top of the bragg reflector, then the film is patterned (e.g. pentagonally or triangularly patterned) by photolithography and plasma etching, then the piezoelectric layer is deposited by PVD, which is an AlN film with a thickness of 1000nm on top of the BE, with a crystallographic 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, wherein the Au electrode and the underlying Cr adhesive layer have a thickness of about 300nm and about 50nm, respectively. The electrode area is configured to be 20,000 μm 2 so 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.
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.
Preparation of isolated mouse skin
Healthy SD rats weighing about 200 grams were anesthetized with pentobarbital, and after careful subtraction of abdominal hair with small scissors, shaved with a razor and avoided skin scarfing, the abdominal skin was peeled off, the skin was spread on a glass plate with stratum corneum facing down, and subcutaneous fat and connective tissue were scraped with saline cotton balls. Washing with physiological saline, soaking in physiological saline, and taking on the same day.
Example 2 penetration of 4000 molecular weight dextran into RC-1000 membranes
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 4000 was prepared in PBS (pH 7.4, gibco, thermo FISHER SCIENTIFIC) to 2mg/ml, 30ul was injected into the liquid supply tank, the top was sealed with RC-1000 membrane (JMD 38, solarbio), and then the receiving tank was pressed against the liquid supply tank with the semipermeable membrane interposed therebetween, and 300ul of PBS was injected into the receiving tank. The effect of dextran on the regenerated cellulose membrane was measured on the control and powered conditions of the non-powered ultra-high frequency acoustic resonator to generate bulk acoustic waves, respectively, and 50ul was sampled at 30, 60, 90 minutes, respectively. The ultra-high frequency acoustic wave resonator has a power condition of 500mW, a frequency of 2.58GHz,0.5S pressurizing pulse and 0.5S interval. Each set of experiments was repeated 3 times.
The content was measured by fluorescent labeling. A commercial fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) was prepared as a mother solution of 2mg/ml, and diluted 12 times in order of 2 times to obtain a standard solution of 0.0005-2 mg/ml. And (3) sequentially measuring and establishing a concentration linear standard curve by adopting a fluorescence quantitative enzyme-labeling instrument (SpectraMax Gemini EM). And placing the experimental sampling sample in a hole of a plate to be measured to read a fluorescence value, and determining the concentration of the sample to be measured by referring to a concentration standard curve.
A method for measuring molecular weight. Dextran (CM-Dextran, SIGMA) sold in the market with different molecular weights of 1000, 5000, 15000, 50000, 200000, 500000 and the like is prepared into a mother solution with the concentration of 2mg/ml, water, methanol=98:2 is sequentially injected into the mother solution as a hydraulic phase, and a liquid phase analysis system (Agilent 1260) with a PL aquagel MIXED-D gel column (Agilent ltd.) and a differential refraction detector is arranged, wherein the flow rate is 1 ml/mm. And establishing a standard curve according to the linear relation between the peak-out time and the molecular weight. The experimentally sampled samples were injected into a liquid phase analysis system and the molecular weight of the samples was determined from the standard curve by retention time.
The results are shown in Table 1 and demonstrate that the effect of the extreme sound waves promotes the permeation of 4000 molecular weight substances through semipermeable membranes having a molecular weight cutoff greater than 1000.
TABLE 1 results of Tab.acoustic wave-fostered 4000 molecular weight dextran permeabilizing RC-1000 membranes
-Indicating that it was undetected due to too low a concentration.
Example 3 pro-40000 molecular weight dextran permeance RC-1000 Membrane
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 40000 was used to prepare a 2mg/ml test solution. The experiment was performed using the same experimental setup and parameters as in example 2.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 2 and demonstrate that the effect of the ultra sonic waves promotes the permeation of 40000 molecular weight materials through semipermeable membranes having a molecular weight cutoff greater than 1000.
TABLE 2 results of ultra sonic wave-fostered 40000 molecular weight dextran permeant RC-1000 film
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 4 penetration of 500000 molecular weight dextran into RC-1000 membranes
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 500000 was prepared as a 2mg/ml test solution. The experiment was performed using the same experimental setup and parameters as in example 2.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 3 and demonstrate that the effect of the extreme sound waves promotes the permeation of 500000 molecular weight substances through semipermeable membranes having a molecular weight cutoff greater than 1000.
TABLE 3 results of ultra sonic wave fostering penetration of 500000 molecular weight dextran through RC-1000 membranes
-Indicating that it was undetected due to too low a concentration.
Example 5A 4000 molecular weight dextran permeant EC-1000 film
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 4000 was prepared as a 2mg/ml test solution, 30ul was injected into the liquid supply tank, the liquid supply tank was capped with a cellulose ester film EC-1000 film (MD 31, spectrumlabs, and a receiving tank was tightly pressed against the liquid supply tank, and PBS 300ul was injected into the receiving tank. The effect of the Dextran on the cellulose ester-permeable film was measured under the conditions of no power control and power, respectively, 50ul was sampled at 30, 60, 90 minutes, the power condition was 500mW, the frequency was 2.58GHz, and the pressurizing pulse was 0.5S, 0.5S intervals. Each experiment was repeated 3 times.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 4, and demonstrate that the effect of the extreme sound waves promotes the permeation of 4000 molecular weight substances through the semipermeable membrane of cellulose ester membranes having a molecular weight cutoff of greater than 1000.
TABLE 4 results of ultra sonic wave-fostered 4000 molecular weight dextran permeant EC-1000 film
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 6 penetration of 500000 molecular weight dextran into RC-1000 membranes
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 500000 was prepared as a 2mg/ml test solution. The experiment was performed using the same experimental setup and parameters as in example 5.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 6, and demonstrate that the effect of the extreme sound waves promotes the permeation of 500000 molecular weight substances through the semipermeable membrane of cellulose ester membranes having a molecular weight cut-off of greater than 1000.
TABLE 5 results of ultra sonic stimulation of 500000 molecular weight dextran permeant EC-1000 films
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 7 insulinotropic RC-1000 film
30Ul of commercially available insulin injections (300 IU/3ml, norhe ling 30R, danish and Norde) were injected into the reservoir connected to the device, capped with RC-1000 membrane (JMD 38, solarbio), and the receiving reservoir was pressed against the reservoir closely across the semipermeable membrane, and PBS 300ul was injected into the receiving reservoir. The transdermal effect of insulin was measured on the unpowered activated ultra-high frequency acoustic resonator and powered condition, respectively, as control and test samples. 50ul samples were taken at 30, 60, and 90 minutes in sequence, with a power condition of 500mW, a frequency of 2.58GHz, and 0.5S pressurizing pulses, 0.5S intervals. Each set of experiments was repeated 3 times.
The insulin content measuring method comprises the steps of using octadecylsilane chemically bonded silica as a filler (5-10 mu m), using 0.2mol/L sulfate buffer (28.4 g of anhydrous sodium sulfate is taken, adding 1.7ml of phosphoric acid after dissolving in water, regulating the pH value to 2.3 by ethanolamine, adding water to 1000 ml) -acetonitrile (74:26) as a mobile phase, and using the column temperature of 40 ℃ and the detection wavelength of 214nm. Taking 20 μl of the system applicability solution (taking insulin reference substance, adding 0.01mol/L hydrochloric acid solution for dissolving and diluting to obtain solution containing about 40 units per 1ml, standing for at least 24 hr), injecting into liquid chromatograph, recording chromatogram, separating insulin peak from A21 deaminated insulin peak (relative retention time of insulin peak is about 1.2) to be no less than 1.8, and tailing factor to be no more than 1.8. Precisely measuring 20 mu 1, injecting into liquid chromatograph, recording chromatogram, taking insulin reference substance, and measuring by the same method. And calculating the content by the sum of the insulin peak area and the A21 deaminated insulin peak area according to an external standard method.
The results are shown in Table 7, and demonstrate that the effect of the extreme sound waves promotes insulin permeation through the semipermeable membrane of regenerated cellulose membranes having a molecular weight cut-off greater than 1000.
TABLE 6 results of ultra sonic insulinotropic films
EXAMPLE 8 Effect of ultra high frequency bulk Acoustic wave Power Change on insulin-permeable RC-1000 film
Experiments were performed using the same experimental setup and parameters as in example 7 to test the effect of different powers activating the ultra-high frequency acoustic wave resonator. The power is 500mW, 800mW, 1000mW and 2000mW respectively. Each set of experiments was repeated 3 times. The insulin content was measured in the same manner as in example 7, and the results are shown in Table 8.
TABLE 7 results of the influence of different power of specific sound waves on insulinotropic RC-1000 membranes
The results show that the penetration promoting effect of the special sound wave is synchronously improved along with the increase of the power within a certain range.
EXAMPLE 9 Effect of multichip combination on insulin-permeable RC-1000 film
Experiments were performed using the same experimental setup and parameters as in example 7 to test the effect of using multiple ultra-high frequency acoustic resonators at the bottom of the same fluid supply tank. And 1, 2,4 and 8 ultrahigh frequency acoustic wave resonators are respectively arranged on a circuit board at the bottom of the liquid supply tank. Each set of experiments was repeated 3 times. The results are shown in Table 10.
TABLE 8 results of the effect of different numbers of chip combinations on insulinotropic RC-1000 film by specific sound waves
The result shows that the penetration promoting effect of the ultra-sound wave is synchronously improved along with the increase of the quantity of the ultra-sound wave nano microchip.
Example 10 promotion of penetration of 4000 molecular weight dextran into rat skin
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 4000 was prepared as a 2mg/ml test solution, 30ul was injected into the supply tank, the SD rat prepared according to the method described in example 1 was capped on the skin ex vivo, and the receiving tank was pressed against the supply tank closely across the skin ex vivo of the SD rat, and 300ul of PBS was injected into the receiving tank. The skin penetration effect of dextran was measured on the control of the bulk acoustic wave generated by the un-powered activated ultra-high frequency acoustic wave resonator and on the powered condition of 500mW, 2.58GHz,0.5S pressurizing pulse, 0.5S interval, respectively, for 50ul samples at 30, 60, 90 minutes. Each set of experiments was repeated 3 times.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 9 and demonstrate that the effect of the extreme sound waves can promote the penetration of dextran of molecular weight 4000 through the rat skin.
TABLE 9 results of ultra-sonic wave-fostering 4000 molecular weight dextran penetration into SD rat skin
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 11 penetration of 40000 molecular weight dextran into rat skin
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) with a molecular weight of 40000 was used to prepare a 2mg/ml test solution. The experiment was performed using the same experimental setup and parameters as in example 10.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 10 and demonstrate that the effect of the extreme sound waves can promote the penetration of dextran of molecular weight 40000 through rat skin.
TABLE 10 results of ultra sonic wave fostering 40000 molecular weight dextran penetration into SD rat skin
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 12 penetration of 500000 molecular weight dextran into rat skin
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, SIGMA) having a molecular weight of 500000 was prepared as a 2mg/ml test solution. The experiment was performed using the same experimental setup and parameters as in example 10.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 11. The results indicate that the effect of the extreme sound waves can promote the penetration of dextran with molecular weight 500000 through the rat skin.
TABLE 11 results of ultra sonic wave stimulation of 500000 molecular weight dextran penetration into rat skin
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 13 insulinotropic rat skin
30Ul of commercially available insulin injections (300 IU/3ml, norhe ling 30R, danish and Norde) were injected into a supply tank connected to the device, SD rats prepared according to the method described in example 1 were capped on the skin ex vivo, and a receiving tank was tightly pressed against the supply tank, into which 300ul of PBS was injected. The skin penetration effect of dextran was measured on the control of the bulk acoustic wave generated by the un-powered activated ultra-high frequency acoustic wave resonator and on the powered condition of 500mW, 2.58GHz,0.5S pressurizing pulse, 0.5S interval, respectively, for 50ul samples at 30, 60, 90 minutes. Each set of experiments was repeated 3 times.
The results of the insulin content measurement are shown in Table 12, which shows that the effect of the ultra-sonic waves can promote insulin permeation through rat skin.
TABLE 12 results of ultra-sonic insulinotropic stimulation of SD rat skin
EXAMPLE 14 Effect of Power Change on insulin-permeable rat skin
Experiments were performed using the same experimental setup and parameters as in example 13 to test the effect of different powers activating the ultra-high frequency acoustic wave resonator. The power is 500mW, 800mW, 1000mW and 2000mW respectively. Each set of experiments was repeated 3 times. The insulin content was measured in the same manner as in example 7, and the results are shown in Table 13.
TABLE 13 results of the effect of different power of the ultra-sonic waves on the skin of insulinotropic rats
The result shows that the penetration promoting effect of the special sound wave is synchronously improved along with the increase of the power within a certain range.
EXAMPLE 15 Effect of multichip combination on insulin-permeable rat skin
Experiments were performed using the same experimental setup and parameters as in example 13 to test the effect of using multiple ultra-high frequency acoustic resonators at the bottom of the same fluid supply tank. And 1,2, 4 and 8 ultrahigh frequency acoustic wave resonators are respectively arranged on a circuit board at the bottom of the liquid supply tank. Each set of experiments was repeated 3 times. The results are shown in Table 14.
TABLE 14 results of the effects of different numbers of chip-combined specific sound waves on insulinotropic rat skin
The result shows that the penetration promoting effect of the ultra-sound wave is synchronously improved along with the increase of the quantity of the ultra-sound wave nano microchip.
EXAMPLE 16 penetration of 40000 molecular weight dextran through EC-1000 Membrane into rat skin
A commercially available fluorescence-labeled Dextran (FITC-CM-Dextran, sigma) with a molecular weight of 40000 was prepared as a 2mg/ml test solution, 30ul was injected into the supply tank, capped with RC-1000 membrane (JMD 38, solarbio), then covered with SD rat ex-vivo skin prepared according to the method described in example 1, and then the receiving tank was pressed against the supply tank with the SD rat ex-vivo skin in between, and PBS 300ul was injected into the receiving tank. The skin penetration effect of dextran was measured on the control and power conditions of the ultra-high frequency acoustic resonator, which was not powered to activate the bulk acoustic wave, and 50ul was sampled at 30, 60, and 90 minutes, respectively. The ultra-high frequency acoustic wave resonator has a power condition of 500mW, a frequency of 2.58GHz,0.5S pressurizing pulse and 0.5S interval. Each set of experiments was repeated 3 times.
The content and molecular weight were measured in the same manner as in example 2. The results are shown in Table 15, and demonstrate that the effect of the ultra-sonic waves promotes the passage of 40000 molecular weight substances through the semipermeable membrane having a molecular weight cutoff of greater than 1000 and through the skin of rats.
TABLE 15 ultra sonic wave fostering 40000 molecular weight dextran permeabilizing RC-1000 membranes and rat skin results
-Indicating that it was undetected due to too low a concentration.
EXAMPLE 17 Effect of insulin penetration of rat skin and Extra-ultrasound frequency through semipermeable Membrane
30Ul of commercially available insulin injections (300 IU/3ml, norhe ling 30R, danish and Norde) were injected into a liquid supply tank connected to the device, capped with RC-1000 membrane (JMD 38, solarbio), covered with SD rat ex vivo skin prepared according to the method described in example 1, and then a receiving tank was pressed against the liquid supply tank with the SD rat ex vivo skin in between. The transdermal effects of insulin were measured on unpowered and powered conditions, control and test samples, respectively. 50ul samples were taken at 30, 60, and 90 minutes in sequence, with 500mW power conditions, 1.31GHz, 1.82GHz, and 2.58GHz, 2.84GHz,3.54GHz,0.5S pressurized pulses at 0.5S intervals. Each set of experiments was repeated 3 times. The insulin content was measured in the same manner as in example 7, and the results are shown in Table 16.
TABLE 16 results of the effect of different frequencies of the ultra-sonic waves on insulinotropic rat skin
EXAMPLE 18 evaluation of transdermal efficacy of insulinotropic agent in rats
Male rats weighing about 200g SD were used, were freely drunk and fed, and were changed for litter every day. Before the start of the experiment, all rats were subjected to adaptive feeding for 3 days under study conditions, marked and weighed, and the STZ (streptozotocin) dose required for diabetic modeling was calculated for each rat based on a dose of 45 mg/kg. 100mg of STZ was dissolved in citrate buffer (pH=4.0, sterile by means of a tunica media) and corresponding doses of STZ solution were injected by tail vein according to the body weight of different SD rats. After 4 days, all rats were subjected to intravenous injection for blood glucose measurement, and the average blood glucose was above 16.7mmol/L, indicating successful modeling of diabetes.
A commercially available insulin injection (300 IU/3ml, norhe ling (30R), danish and Norde) was injected into the liquid supply tank (300 ul), the liquid supply tank was tightly sealed with RC-1000 membrane (JMD 38, solarbio), the liquid supply tank was fixed to the abdomen of a rat anesthetized with diethyl ether, and one side of the RC-1000 membrane of the liquid supply tank was in contact with the abdomen. The transdermal effect of insulin was measured on the conditions of no power applied to activate the ultra-high frequency acoustic resonator to generate bulk acoustic waves and power applied, respectively, as control and test samples. The power condition is 500mW, 2.58GHz,0.5S pressurizing pulse, 0.5S interval, and drug release is carried out for 90 minutes. The change in blood glucose was measured at 2, 4, 6, 8, 10, 12 hours, and compared with the synchronous blood glucose of the normal anesthetized non-administered group, an equivalent amount of intravenous insulin group was additionally set to the positive control. Each set of experiments was repeated 3 times. The results are shown in Table 17.
TABLE 17 results of in vivo experiments of ultra sonic insulinotropic rat skin
Experiments show that under the same conditions, compared with a control group of the ultra-high frequency acoustic wave resonator activated without power, the power-added group can obviously reduce the blood sugar content in animals, which shows that the transdermal effect is obvious. Compared with the intravenous injection administration group, the power-added group has the effect of sustained drug release, and can maintain remarkable blood sugar reducing effect within 8 hours, and the intravenous injection administration group loses the effective blood sugar reducing effect after 2 hours and reaches the maximum blood sugar reducing effect after 4 hours. Therefore, the blood glucose reducing effect of the ultrasonic wave transdermal promoting method and device has the characteristics of high efficiency and long acting, and has obvious advantages compared with the prior art.
The present invention provides a new method and apparatus for transdermal delivery of biologically active substances, particularly drug molecules that are not readily or transdermally permeable, using a ultra-high frequency resonator to generate bulk acoustic waves. The inventors have unexpectedly found that the ultra-high frequency resonator produces bulk acoustic waves that effectively pass small molecule compounds and proteins through semi-permeable membranes, and even through the skin of the animal body, thereby providing a method and apparatus for safely and conveniently delivering small molecule chemicals, polypeptide drugs, and biological drugs such as antibodies and vaccines. The inventors have also addressed a method of making an active substance present in a liquid into a delivery composition and device comprising encapsulation by translucency.
Although exemplary embodiments of the present invention and their 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 remaining within the scope of the present invention.
Furthermore, 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. From the present disclosure, it will be readily understood by those of ordinary skill in the art that 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 disclosure. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
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