The application relates to an administration device, in particular to an iontophoresis administration device.
Percutaneous administration refers to a method of administration on a skin surface to allow a medicament to pass through the skin at a certain rate and enter systemic circulation to produce systemic or local therapeutic effect. Because the percutaneous administration method has the advantages of not being affected by factors such as food in the digestive tract and continuously controlling the administration rate, it has broad application prospects.
In the process of percutaneous administration, the skin stratum corneum has a barrier function, which makes it difficult for the current penetration rate and penetration amount through the skin surface to achieve expected effect. A traditional scheme for improving the penetration rate and penetration amount is, for example, a microneedle percutaneous administration method, that is, a microneedle array is set on an administration carrier to make the microneedles penetrate the skin stratum corneum, thereby improving the penetration rate of the percutaneous administration method. The above-mentioned microneedle percutaneous scheme has relatively high requirements for the length of the microneedles, and if they are not well controlled, it is easy to damage the skin and cause pain.
Another traditional scheme for improving the percutaneous administration is, for example, an iontophoresis administration method, that is, a non-invasive method that uses charged charges to push active medicaments with polarity into the skin by electromotive force. In the traditional iontophoresis administration method, electrically driving single-point electrode or multiple administration carriers with electrodes are usually set for administration. The above iontophoresis administration method either has no obvious penetration effect or is easy to cause the skin burns.
Therefore, the traditional percutaneous administration schemes have some shortcomings: either the penetration effect is not obvious, or they are easy to cause the skin burns or pain and other skin injuries.
According to exemplary embodiments of the present disclosure, there is provided an iontophoresis administration device that not only can improve the penetration efficiency, but also does not cause skin injury easily.
In a first aspect of the present disclosure, there is provided an iontophoresis administration device. The device comprises: a power supply for generating electricity required to penetrate a medicament to be penetrated into an administered area of an organism; an integrated dielectric layer for covering the administered area, wherein the integrated dielectric layer comprises: a gel, and the polar, free-state medicament to be penetrated; and a plurality of electrodes for electrically connecting with the power supply and the integrated dielectric layer respectively, such that the electricity generated by the power supply flows through the administered area and at least part of the integrated dielectric layer respectively, wherein the at least part of the integrated dielectric layer has a predetermined resistance value.
In some embodiments, the gel comprises at least one of the following components: polyethylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polymethacrylic acid, gelatin, alginic acid.
In some embodiments, the plurality of electrodes are a plurality of flexible conductive electrode films separated by a predetermined interval.
In some embodiments, the medicament to be penetrated comprises vitamin C and arbutin.
In some embodiments, the medicament to be penetrated comprises vitamin C and tranexamic acid.
In some embodiments, the medicament to be penetrated has a molecular weight less than or equal to 10,000 daltons.
In some embodiments, the thickness of the integrated dielectric layer is less than or equal to 50 mm.
In some embodiments, the electricity is an alternating current and the current intensity of the electricity is less than or equal to 5 mA.
In some embodiments, the electricity is a direct current and the current intensity of the electricity is less than or equal to 5 mA.
In some embodiments, the current intensity of the electricity is greater than or equal to 0.01 mA.
In some embodiments, the power supply comprises at least a first power supply, and the plurality of electrodes comprises at least a first electrode and a second electrode, wherein the first electrode is electrically connected with a first end of the first power supply and the second electrode is electrically connected with a second end of the first power supply.
In some embodiments, the power supply further comprises a second power supply, and the plurality of electrodes further comprises a third electrode and a fourth electrode, wherein the third electrode is electrically connected with a first end of the second power supply and the fourth electrode is electrically connected with a second end of the second power supply.
In some embodiments, the power supply further comprises a third power supply and a fourth power supply, the plurality of electrodes further comprises a fifth electrode, a first end of the third power supply is electrically connected with the second end of the first power supply, a second end of the third power supply is electrically connected with the fifth electrode, a first end of the fourth power supply is electrically connected with the first end of the first power supply, and a second end of the fourth power supply is electrically connected with the second end of the third power supply.
In some embodiments, the iontophoresis administration device further comprises a back substrate layer for covering the plurality of electrodes, and the back substrate layer is an insulation material; and a plurality of connectors for electrically connecting the power supply and the plurality of electrodes respectively, each of the plurality of connectors is at least partially disposed in the back substrate layer.
In some embodiments, the predetermined resistance value is greater than 100 ohms and less than or equal to 100K ohms.
In some embodiments, the predetermined resistance value is greater than 1K ohms and less than or equal to 12K ohms.
In some embodiments, the gel comprises collagen.
It should be understood that the contents described in the summary section are not intended to limit key or important features of the embodiments of the present disclosure nor intended to limit the scope of the present disclosure. Other features of the present disclosure will be readily understood by the following description.
The above and other features advantages and aspects of various embodiments of the present disclosure will become more apparent when taken in conjunction with the accompanying figures and with reference to the following detailed description. In the figures, identical or like reference numerals indicate identical or like elements, wherein:
In the various figures, the same or corresponding reference numerals indicate the same or corresponding parts.
Embodiments of the present disclosure will be described in more detail below with reference to the accompanying figures. While certain embodiments of the present disclosure are shown in the accompanying figures, it should be understood that the present disclosure may be embodied in various forms and should not be construed as being limited to the embodiments set forth herein, on the contrary these embodiments are provided for a more thorough and complete understanding of the present disclosure. It should be understood that the figures and embodiments of the present disclosure are for exemplary purposes only and are not intended to limit the scope of protection of the present disclosure.
In the description of embodiments of the present disclosure, the term “comprising” and similar terms should be understood as open comprising, i.e., “comprising but not limited to”. The term “based” should be understood as “based at least in part”. The term “an embodiment” or “the embodiment” should be understood as “at least one embodiment”. The terms “first”, “second”, etc. may refer to different or identical objects. Other definitions, both explicit and implicit, may be included below.
As mentioned above traditional iontophoresis administration scheme is for example provided with a single electrode or multiple administration carriers each with electrode, the electrode is electrically connected with a power supply. Before administration, measuring skin resistance of the organism to be administered, and setting a safe power supply voltage and current according to the measured resistance, or setting a safe power supply voltage and current according to a general empirical value of the skin resistance, so as to ensure that the skin of the organism to be administered is not injured.
In the above-mentioned traditional iontophoresis administration scheme, on the one hand, with the advancement of the administration process, skin state (such as water content and medicament amount accumulated in the skin) of the administrated area will change. At the same time, the skin resistance of the administrated area also changes as the skin state changes. Therefore, the power supply voltage and current value set before administration do not take into account the change amount of the skin resistance during administration, therefore, it will not be compatible with the changed skin resistance during the administration. For example, during the administration process, the water content or the medicament amount in the skin increases, and the skin resistance decreases. When the preset power supply voltage remains unchanged, the current intensity flowing through the skin will increase, which is likely to cause irritation and burns to the skin.
To address at least one of the above problems and one or more of other potential problems, embodiments of the present disclosure propose an iontophoresis administration device. The device comprises: a power supply for generating electricity required to penetrate a medicament to be penetrated into an administered area of an organism; an integrated dielectric layer for covering the administered area, wherein the integrated dielectric layer comprises: a gel, and the polar, free-state medicament to be penetrated; and a plurality of electrodes for electrically connecting with the power supply and the integrated dielectric layer respectively, such that the electricity generated by the power supply flows through the administered area and at least part of the integrated dielectric layer respectively, wherein the at least part of the integrated dielectric layer has a predetermined resistance value.
In the iontophoresis administration device provided by the present disclosure, since the electricity generated by the power supply is caused to flow through the administered area and the at least part of the integrated dielectric layer having the predetermined resistance value respectively, that is, by connecting the integrated dielectric layer having the predetermined resistance value in parallel with the skin resistance of the administered area, the current flowing through the administered area is shunted, thereby avoiding excessive current intensity irritation or burns to the skin. In addition, according to the principle of the parallel circuit, the ratio of the current shunted by the dielectric layer is related to the ratio between the predetermined resistance value of the dielectric layer and the skin resistance of the administration area. Therefore, when the resistance value of the dielectric layer is constant, the current shunted by the dielectric layer also changes as the skin resistance of the administration area changes. Since the skin state changes as different individuals are different, therefore the iontophoresis administration device of the present disclosure can not only solve the technical problems of irritation or burns to the skin caused by the increase of the current intensity caused by the decrease of the skin resistance in the administration process, moreover can adaptively adjust the current flowing through the skin according to the different skin conditions of different individuals, in a simple and convenient way. Furthermore, in the iontophoresis administration device, since a part of the current flows through the integrated dielectric layer which is between the electrodes, contains the gel with the free-state medicament, and has the predetermined resistance value, the integrated dielectric layer and its gel covering the surface of the administered area will generate heat. The epidermis comprises a stratum corneum, a granular layer, a spinous layer and a basal layer from outside to inside. The key to percutaneous absorption in the epidermis lies in “skin barrier”. The skin barrier comprises a stratum corneum and a sebum film. Under normal circumstances, appropriate increase in skin temperature is beneficial to improving the efficiency of the medicament to be penetrated penetrating the “skin barrier”. Therefore, the heat generated by the current flowing through the integrated dielectric layer is beneficial to improve the efficiency of the medicament to be penetrated through the “skin barrier”.
With respect to the power supply 110, it is used to generate electricity required to penetrate the medicament to be penetrated into the administered area. In some embodiments, the iontophoresis administration device 100 comprises one power supply. In some embodiments, the iontophoresis administration device 100 comprises a plurality of power supplies. The plurality of power supplies may be connected in series and/or in parallel with each other for providing appropriate voltage and current to penetrate the medicament to be penetrated into the administered area. The electricity generated by the power supply 100 may be constant or variable. In some embodiments, the settings of the power supply time, the power supply voltage, and the current intensity of the power supply are associated with the dosage of the medicament to be penetrated. In some embodiments, the power supply voltage amplitude, the current intensity, the power supply time, the frequency, the duty cycle, etc. of the power supply are adjusted according to the size of the dosage, different administration modes (e.g., instantaneous dosage administration mode, constant administration mode, pulse administration mode, etc.).
In some embodiments, the electricity provided by the power supply 110 is an alternating current. This is because, on the one hand, direct current is easy to cause local anesthetic effect on the skin, which is easy to cause imperceptible skin injury to the medicament recipient, and on the other hand, direct current is easy to cause the accumulation of electric charge in the skin layer, which in turn leads to a decrease in the rate and total amount of the medicament to be penetrated 130 delivered over time. By alternating current direction of the alternating current provided by the power supply 110, the accumulation of capacitive charge in the skin layer can be solved, thereby facilitating the improvement of the penetration efficiency and the total amount of the medicament. In some embodiments, the current intensity of the alternating current is less than or equal to 5 mA. In some embodiments, the current intensity of the alternating current is greater than or equal to 0.01 mA and less than 5 mA, and the current intensity is set in a range that not only avoids skin injury, but also ensures sufficient electrical potential energy required to penetrate the medicament to be penetrated into the administered area.
With regard to the electrodes 112, they are configured as ion penetration electrodes. The plurality of electrodes 112 are used to connect two output ends of the power supply 110 to the integrated dielectric layer 114 respectively, so that the electricity generated by the power supply flows through the administered area and at least part of the integrated dielectric layer respectively. For example, as shown in
As far as the administered subjects are concerned, due to differences of individual skin (for example, differences in the ratio of water to oil, dryness, pores, etc.), there are certain differences in individual skin resistance values. Because the current flowing through the skin may burn the skin due to the heat generated by the skin resistance value, in order to avoid causing injury to the skin of the administered object, the traditional iontophoresis administration scheme usually strictly limits the output current intensity based on the skin resistance value under extreme condition, which will lead to the side effect of reducing the percutaneous administration efficiency. In the above scheme of the present disclosure, by covering the integrated dielectric layer 130 which is integral, has the predetermined resistance value and contains the polar, free-state medicament to be penetrated under the plurality of independent electrodes 112, shunting the current flowing through the skin of the administered area 122 by utilizing the integrated dielectric layer in parallel with the skin resistance of the administered area 122, thereby reducing the current intensity flowing through the skin and effectively avoiding skin irritation or burns under a given power supply voltage.
With respect to the predetermined resistance value of the integrated dielectric layer 114, it is assumed that the resistance of the integrated dielectric layer through which current flows is R1 and the skin resistance of the administered area 122 is R2. According to the principle of resistance parallel connection, if R1>R2, most of the current provided by the power supply is used to activate the active substances in the skin. If R1<R2, most of the current provided by the power supply is used to push the active substance dispersed in the gel into the skin. In some embodiments, R1 is set to 10%-90% of R2. In some embodiments, R1 is set to be greater than 100 ohms and less than or equal to 100K ohms, and in some embodiments, R1 is set to be greater than 1K ohms and less than or equal to 12K ohms, e.g., 10K ohms.
With respect to the electrodes 112, they may be sheet-shaped electrodes, dot-shaped electrodes, layered electrodes or another shapes. In some embodiments, the plurality of electrodes 112 are a plurality of flexible conductive electrode films separated by a predetermined interval. The conductive electrode film is, for example, a low-resistance conductive film, a conductive carbon film, and a carbon-based conductive film. The flexible conductive electrode film is prepared by mixing polyethylene with polymer superconducting nano carbon black, curing medicament, auxiliary medicament and the like. The ion penetration electrodes are arranged in the form of flexible conductive electrode films, which have the advantages of uniform and stable resistance value, good bending performance and flexibility performance, and are beneficial to make the integrated dielectric layer 114 and the electrodes better fit the different external contour of the administered area, and are not easy to be electric corrosion. Therefore, compared with the traditional sheet-shaped ion penetration electrodes, they have obvious advantages. In some embodiments, the plurality of electrodes in the form of flexible conductive electrode films may be attached to a back substrate layer 116 by an adhesive, and the electrodes in the form of flexible conductive electrode films are separated from each other on the back substrate layer 116 by the predetermined interval. The predetermined interval is, for example, 0.1 to 10 mm, preferably 1 to 2 mm. With this arrangement, the penetration efficiency can be improved by controlling the coverage area of the ion penetration electrodes.
With respect to the gel 118, it comprises for example but not limited to a matrix, an active medicament and an additive. The gel 118 is formed by cross-linking, medicament dispersion, curing and the like. Wherein, the active medicament is the polar and free-state medicament to be penetrated 130. The additive comprises, for example, but not limited to, penetration enhancer, pharmaceutical solvent, etc. In some embodiments, the gel 118 comprises, for example, at least one or more of the following components: polyethylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylic acid, polymethacrylic acid, gelatin, alginic acid. Experiments show that the gel composed of the above components can not only form a polymer cross-linking network structure with certain strength, but also make the medicament to be penetrated dispersed freely in the gel. This arrangement facilitates not only shunting the current flowing through the skin of the administered area 122, but also significantly improving the controlled release effect of the medicament to be penetrated 130. The experimental results show that after penetration administration of the gel provided by the present disclosure, administration concentration of the medicament 130 can be stable, and the bio-availability is ideal.
With respect to the medicament to be penetrated 130, it is for example but not limited to the medicament for pain relief, treatment of arthritis or asthma, hormone regulation, cosmetic and the like purposes. In some embodiments, the medicament to be penetrated 130 has a molecular weight less than or equal to 10,000 daltons. This is because studies have shown that the medicament to be penetrated 130 with molecular weight less than or equal to 10,000 daltons can easily enter the skin through intercellular space, which is beneficial to improve the penetration efficiency. For example, the polar, free-state medicament 130 with molecular weight less than or equal to 10,000 daltons is uniformly dispersed in the gel 118, released from the gel 118 under the action of the charge provided by the electrode 112, diffused to the skin stratum corneum, and then extended to the dermis through the epidermis and even into the capillaries of the skin.
In some embodiments, the medicament to be penetrated 130 comprises vitamin C and arbutin. The arbutin in the medicament to be penetrated 130 is beneficial to inhibit tyrosinase in the skin, block melanin formation, accelerate melanin decomposition and excretion, and has anti-inflammatory effect at the same time. The vitamin C in the medicament to be penetrated 130 has antioxidant effect, which is beneficial to inhibit the formation of pigment spots and promote the regression of pigment spots. Experiments show that, the medicament to be penetrated 130 comprises both vitamin C and arbutin components, and is polarized and uniformly dispersed in a free-state in the gel 118 of the integrated dielectric layer 114, an electric current is applied via an electrode of the iontophoresis administration device 100 so that the polar, free-state medicament to be penetrated 130 is introduced into the administrated area 122, and the administrated area 122 and the surrounding area can be rapidly whitened, and the whitening effect can last for a considerable period of time. In some embodiments, the medicament to be penetrated 130 containing vitamin C and arbutin is uniformly distributed in the gel 118 of an integrated dielectric layer 114 disposed in the shape of a facial mask for whitening the human face by iontophoresis.
In some embodiments, the medicament to be penetrated 130 comprises vitamin C and tranexamic acid. The tranexamic acid in the medicament to be penetrated 130 is used to inhibit tyrosinase activity, thereby inhibiting melanin formation. Experiments show that, the medicament to be penetrated 130 comprises both vitamin C and tranexamic acid components, and is polarized and uniformly dispersed in a free-state in the gel 118 of the integrated dielectric layer 114, and an electric current is applied through the electrode of the iontophoresis administration device 100, so that the polar, free-state medicament 130 to be penetrated is introduced into the administrated area 122, and dark spots in the administrated area 122 can be effectively removed. In some embodiments, the medicament to be penetrated 130 containing vitamin C and tranexamic acid is uniformly distributed in the gel 118 of the integrated dielectric layer 114 disposed in the shape of a facial mask for freckle removal of a human face by iontophoresis.
In some embodiments, the iontophoresis administration device 100 further comprises a back substrate layer 116 for overlaying the plurality of electrodes 112, the back substrate layer 116 is an insulation material. The plurality of connectors 111-1 and 111-2 are used for electrically connecting the corresponding electrodes to the power supply respectively, each of the plurality of connectors 111-1 and 111-2 is at least partially disposed in the back substrate layer 116.
The plurality of connectors 211-1 and 211-2 made of a conductive material are provided on the back substrate layer 216, each connector being at least partially provided in the back substrate layer 216 for coupling the electricity from the power supply to corresponding flexible conductive electrode films 212-1 and 212-2. Connection modes between the connector and the power supply or the wire connected to the power supply may be in various ways, such as but not limited to mechanical coupling connection such as snap connection, magnet action connection, bonding or welding. The connection modes of the snap connection and the magnet action connection are convenient for adjusting the connection mode between power supply and electrodes. For example, each connector 211 is a pair of connector components (not specifically shown) that can be snap-coupled, one connector component is connected to the wire connected to the power supply, and the other connector component is connected to a flexible conductive electrode film. Through the snap coupling of the two connector components, the electrical connection between the wire connected to the power supply and the flexible conductive electrode film is realized. For another example, each connector 211 is a pair of magnet connector components (not specifically shown) capable of attracting each other, one magnet connector component is connected to the wire connected to the power supply, and the other magnet connector component is connected to a flexible conductive electrode film. The two magnet connector components are jointed together by magnet action, thereby realizing electrical connection between the wire connected to the power supply and the flexible conductive electrode film.
As shown in
As shown in
In the above scheme, by connecting two or more power supplies in series, the voltage amplitude required for iontophoresis administration can be adjusted. By connecting two or more power supplies in parallel, the current intensity required for iontophoresis administration can be adjusted. The first electrode 412-1, the second electrode 412-2, and the fifth electrode 412-5 are respectively connected to different output ends of the power supplies connected in series and parallel to each other, so that the electric parameters of iontophoresis administration between the first electrode 412-1 and the second electrode 412-2 and the electric parameters of iontophoresis administration between the second electrode 412-2 and the fifth electrode 412-5 are relatively independent and controllable, and have certain correlation. So as to realize personalized control of percutaneous administration.
As shown in
For example, in a first time period, the controller outputs a high-level first signal to turn on the first switch 540, and simultaneously outputs a low-level second signal to turn off the second switch 542, so that the positive electrode of the first power supply 510-1 is electrically connected with the first electrode 512-1, and the negative electrode of the first power supply 510-1 is electrically connected with the second electrode 512-2, that is, the medicament to be penetrated is introduced with the current in a first direction in the first time period. And in the second time period, the controller outputs a low-level first signal to turn off the first switch 540, and simultaneously outputs a high-level second signal to turn on the second switch 542, so that the negative electrode of the fifth power supply 510-5 is electrically connected with the first electrode 512-1 and the positive electrode of the fifth power supply 510-5 is electrically connected with the second electrode 512-2 in the second time period, that is, the medicament to be penetrated is introduced with the current in a second direction in the second time period. By adopting the above solution, multiple direct current power supplies combining with switches are used to solve the problem of the accumulation of capacitive charges in the skin layer, thereby improving the penetration efficiency and total amount of the medicament.
As shown in
For example, in the third time period, the controller simultaneously turns on the first switch 640 and the second switch 642, and simultaneously turns off the third switch 644 and the fourth switch 646, so that the positive electrode of the first power supply 610-1 is electrically connected with the first electrode 612-1, and the negative electrode of the first power supply 610-1 is electrically connected with the second electrode 612-2, that is, the medicament to be penetrated is introduced with the current in the first direction in the third time period. In the fourth time period, the controller simultaneously turns off the first switch 640 and the second switch 642, and simultaneously turns on the third switch 644 and the fourth switch 646, so that the negative electrode of the first power supply 610-1 is electrically connected with the first electrode 612-1, and the positive electrode of the first power supply 610-1 is electrically connected with the second electrode 612-2, that is, the medicament to be penetrated is introduced with the current in the second direction in the fourth time period. By adopting the above solution, direct current power supplies combining with multiple switches are used to solve the problem of the accumulation of capacitive charges in the skin layer, thereby improving the penetration efficiency and total amount of the medicament.
As shown in
For example, in a first time period, through the control of the controller (not shown), the first power supply 710-1 is turned off (that is, it works in the “OFF” state and does not output current). At the same time, the second power supply 710-2 is turned on (that is, it works in the “ON” state), the output current of the second power supply 710-2 at least partially flows through the second connector 711-2, the second electrode 712-2, at least part of the integrated dielectric layer 714, the third electrode 712-3, and the third connector 711-2 in sequence. (At this time, the positive electrode of the second power supply 710-2 is connected to the second connector 711-2. If the second power supply 710-2 is reversely connected, the current flow sequence will be different). It can be seen that in the first time period, the direction in which the direct current flows in the integrated dielectric layer 714 is as shown by the arrow in the upper half of
For example, in a second time period, through the control of the controller (not shown), the second power supply 710-2 is turned off (that is, it works in the “OFF” state and does not output current) At the same time, the first power supply 710-1 is turned on (that is, it works in the “ON” state), the output current of the first power supply 710-1 at least partially flows through the fourth connector 711-4, the fourth electrode 712-4, at least part of the integrated dielectric layer 714, the first electrode 712-1, and the first connector 711-2 in sequence. It can be seen that in the second time period, the direction in which the direct current flows in the integrated dielectric layer 714 is as shown by the arrow in the lower half of
By adopting the above solution, only direct current power supplies are used to solve the problem of the accumulation of capacitive charges in the skin layer, thereby improving the penetration efficiency and total amount of the medicament.
The embodiments of the present disclosure have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical applications or technical improvements in the market of the embodiments, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
The foregoing descriptions are only optional embodiments of the present disclosure, and are not used to limit the present disclosure. For those skilled in the art, the present disclosure may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.
Number | Date | Country | Kind |
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201910370935.1 | May 2019 | CN | national |
Filing Document | Filing Date | Country | Kind |
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PCT/CN2020/093888 | 6/2/2020 | WO | 00 |