Abstract
The present invention relates to a biodegradable iontophoretic patch and a method for manufacturing the same. The ion patch comprises a drug-loaded gel and a buffering gel, and by adding a pH adjuster to the buffering gel, it is possible to prevent excessive increases in pH during use of the ion patch. Therefore, the invention can be used in the manufacture of ion patches for enhancing skin absorption of cosmetic or pharmaceutical compositions.
Claims
1. An ion patch comprising: an electrode layer including a pair of an anode and a cathode; and gel layers respectively laminated on the anode and the cathode, performing different functions, wherein the gel laminated on the anode is a buffering gel including a pH adjuster, and the gel laminated on the cathode is a drug-loaded gel.
2. The ion patch of claim 1, wherein the ion patch further comprises a frame located beneath the electrodes, and the frame comprises a biodegradable polymer including polybutylene adipate-co-terephthalate (PBAT).
3. The ion patch of claim 1, wherein the cathode and the anode each independently have a thickness of 50 to 400 m.
4. The ion patch of claim 1, wherein the gel layer laminated on the cathode and the gel layer laminated on the anode each independently have a thickness of 0.4 to 2 mm.
5. The ion patch of claim 1, wherein the cathode comprises a biodegradable material capable of a skin-friendly reduction reaction, and includes one or more selected from transition metal oxides, biodegradable metals, and biodegradable polymers.
6. The ion patch of claim 1, wherein the cathode comprises a biodegradable polymer and a crosslinking agent.
7. The ion patch of claim 2, wherein the cathode further comprises a coating layer based on a biodegradable conductive material on a contact surface with the frame.
8. The ion patch of claim 1, wherein the anode comprises a biodegradable metal.
9. The ion patch of claim 1, wherein the electrode layer further comprises a current regulator connecting the cathode and the anode.
10. The ion patch of claim 9, wherein the current regulator comprises a mixture of biodegradable metal particles and a biodegradable polymer.
11. The ion patch of claim 1, wherein the drug-loaded gel comprises at least one selected from the group of biodegradable ionic polymers including alginate, carboxymethyl cellulose (CMC), and dextran sulfate (DS).
12. The ion patch of claim 1, wherein the buffering gel independently comprises at least one selected from the group consisting of agarose, maltose, and glycerol.
13. The ion patch of claim 1, wherein one or more of the drug-loaded gel layer and the buffering gel layer further comprises a skin-adhesive gel layer, and the skin-adhesive gel layer comprises gelatin and an ion-conductive biodegradable polymer.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1a is a schematic view of an ion patch manufactured according to one embodiment of the present invention.
[0067] FIG. 1b is a graph showing current signals measured from ion patches manufactured with varying thicknesses of MoO.sub.3 according to one embodiment of the present invention.
[0068] FIG. 2a is a schematic view and a photograph of an ion patch manufactured with the thickness of MoO.sub.3 paste selected as 300 m according to one embodiment of the present invention.
[0069] FIG. 2b is a graph showing current signals measured from an ion patch manufactured with the thickness of MoO.sub.3 paste selected as 300 m according to one embodiment of the present invention.
[0070] FIG. 2c is a discharge graph measured from ion patches manufactured with or without the addition of citric acid, a crosslinking agent, to a MoO.sub.3 and PAAc (polyacrylic acid) polymer paste according to one embodiment of the present invention.
[0071] FIG. 2d is an image confirming whether diffusion of cathode material occurred due to polymer swelling after discharging for 1 hour at 300 A, in ion patches manufactured with or without the addition of citric acid, a crosslinking agent, to a MoO.sub.3 and PAAc polymer paste according to one embodiment of the present invention.
[0072] FIG. 3a is a schematic view of an ion patch in which the cathode is coated with molybdenum (Mo) according to one embodiment of the present invention.
[0073] FIG. 3b is a graph showing pH value changes under conditions of pH 7.4, as measured from an ion patch with a molybdenum-coated cathode according to one embodiment of the present invention.
[0074] FIG. 3c is a graph showing pH value changes under conditions of pH 5.5, as measured from an ion patch with a molybdenum-coated cathode according to one embodiment of the present invention.
[0075] FIG. 4a is an illustration showing the pH values of the skin surface according to different regions of the human body.
[0076] FIG. 4b is a graph showing pH value changes under conditions of pH 4.2, as measured from an ion patch according to one embodiment of the present invention.
[0077] FIG. 5a is a schematic view of an ion patch for confirming pH control depending on the presence or absence of citric acid, according to one embodiment of the present invention.
[0078] FIG. 5b is a schematic view of an ion patch showing the measurement area for confirming pH control depending on the presence or absence of citric acid, according to one embodiment of the present invention.
[0079] FIG. 6a is a schematic view of an ion patch and a skin model for confirming the drug absorption rate into the skin depending on current density, according to one embodiment of the present invention.
[0080] FIG. 6b is a graph showing the drug absorption rate into the skin from the ion patch depending on current density, according to one embodiment of the present invention.
[0081] FIG. 7a is a schematic view of an electrode structure and a skin model for confirming the drug absorption rate into the skin from the ion patch depending on whether iontophoresis is applied, according to one embodiment of the present invention.
[0082] FIG. 7b is a graph showing the drug absorption rate into the skin from the ion patch depending on whether iontophoresis is applied, according to one embodiment of the present invention.
[0083] FIG. 8a is a graph showing the absorption rate of niacinamide into the skin from the ion patch depending on whether iontophoresis is applied, according to one embodiment of the present invention.
[0084] FIG. 8b is a graph showing the absorption rate of adenosine into the skin from the ion patch depending on whether iontophoresis is applied, according to one embodiment of the present invention.
[0085] FIG. 9a is a schematic view of single-gel and double-gel ion patch models according to one embodiment of the present invention.
[0086] FIG. 9b is a graph showing current intensity in single-gel and double-gel ion patch models according to one embodiment of the present invention.
[0087] FIG. 10a is a graph showing current intensity in a gelatin gel-applied ion patch model according to one embodiment of the present invention.
[0088] FIG. 10b is a graph showing current intensity in an alginate gel-applied ion patch model according to one embodiment of the present invention.
[0089] FIG. 11a is a schematic view of ion patch models with different types of gels applied, according to one embodiment of the present invention.
[0090] FIG. 11b is a graph comparing the ion absorption amounts of gelatin- and alginate-applied ion patch models, according to one embodiment of the present invention.
[0091] FIG. 12a is a schematic view of an ion patch model and a skin model for measuring ion absorption amounts at different skin depths, according to one embodiment of the present invention.
[0092] FIG. 12b is a graph showing ion absorption amounts of a drug-loaded gel, according to one embodiment of the present invention.
[0093] FIG. 13 is a schematic view of an ion patch manufactured according to one embodiment of the present invention.
MODE FOR CARRYING OUT THE INVENTION
[0094] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are provided only for illustrative purposes, and the scope of the present invention is not limited thereto.
[0095] Throughout this specification, unless otherwise stated, % used to indicate the concentration of a specific substance means (weight/weight) % for solid/solid, (weight/volume) % for solid/liquid, and (volume/volume) % for liquid/liquid.
Example 1: Configuration of Ion Patch
[0096] To determine the appropriate thickness for using molybdenum trioxide (MoO.sub.3) as the electrode in the configuration of the ion patch, electrode structures were fabricated with MoO.sub.3 applied at thicknesses of 150, 200, and 400 m, respectively, and the current signal was measured using an ammeter.
[0097] As shown in FIGS. 1a and 1b, as the thickness of MoO.sub.3 increases, the current capacity increases and ion diffusion decreases; thus, a thickness of 200 m was determined to be the most optimal. Subsequently, an ion patch model capable of implementing iontophoretic operation was fabricated using MoO.sub.3 with a selected thickness of 300 m as the cathode, as shown in FIG. 2a, and the current signal was measured.
[0098] As shown in FIG. 2b, the current capacity measured from the ion patch operation model was 0.486 mAh, which is higher than the required iontophoresis threshold of 0.15 mAh, indicating that the model is capable of generating microcurrents within an appropriate range.
Example 2: Ensuring Operational Stability Using a Crosslinking Agent
[0099] In water-electrolyte-based galvanic ion patches, during operation, the cathode composed of electrode material and a polymer binder absorbs moisture due to the hydrophilicity of the polymer, causing swelling and resulting in reduced operational stability. To partially address this issue, a method utilizing a crosslinking agent can be employed.
[0100] As shown in FIG. 2c, a comparison based on the presence or absence of the crosslinking agent citric acid reveals that when no crosslinking agent is used, the polymer binder swells over time, causing the electrode material to detach and spread, leading to unstable electrochemical reactions at the cathode and a resulting decrease in operating voltage. In contrast, when the crosslinking agent is used, the electrode material remains stably fixed within the polymer binder over time, maintaining a stable electrochemical reaction and thereby sustaining the operating voltage.
[0101] As shown in FIG. 2d, when the crosslinking agent is not used, the electrode material diffuses into the electrolyte after operation. In contrast, when the crosslinking agent is used, the electrode material remains fixed even after operation.
Example 3: Conditioning pH Value in the Ion Patch
[0102] During operation, the ion patch may cause an increase in pH at the anode. To partially address this issue, a method of coating the MoO.sub.3 cathode with molybdenum (Mo), as shown in FIG. 3a, can be employed.
[0103] As shown in FIG. 3b, when the pH is 7.4, MgO.sub.2 increases on the anode surface, resulting in the generation of OH.sup. ions in the electrolyte, which in turn increases the pH value. From this result, it can be inferred that suppressing the formation of MgO.sub.2 on the electrode surface may be a way to prevent an increase in pH.
[0104] As shown in FIG. 3c, when the pH is lowered to 5.5, the formation of MgO.sub.2 on the anode surface is suppressed, preventing the generation of OH.sup. ions in the electrolyte, and thus the pH value did not increase.
Example 3: Exploration of Optimal pH Conditions
[0105] As shown in FIG. 4a, based on biocompatibility with reference to the facial area where the ion patch is applied, a pH value of 4.2 is appropriate; accordingly, the application conditions of the electrode structure were adjusted to this pH.
[0106] As shown in FIG. 4b, the results of applying the electrode structure under pH 4.2 conditions showed that the concentration of Mg.sup.2+ ions remained stable, similar to the results under pH 5.5 conditions.
[0107] To control the pH value, 250 mM of citric acid was added to the gel laminated on the anode, and a control group without citric acid was prepared for comparison.
TABLE-US-00001 TABLE 1 Gelatin Citric Citric Acid Gel PBS Glycerol Syrup Acid Concentration pH Citric Acid 8 ml 6.3 ml 6.5 ml 1 g 250 mM 3 Control 8 ml 6.3 ml 6.5 ml 0 g 0 mM 7.4
[0108] The conditions of the electrode structures shown in FIGS. 5a and 5b are as follows: [0109] Current: 100 A [0110] Duration: 1 hour [0111] Volume of gelatin gel: 0.08 cm.sup.3 [0112] Measured amount of OH.sup. generated on the Mg surface: 3.73 mol
Measured Citric Acid Content in the Gelatin Gel:
[0113] (![custom-character]()
: 0 mol; Article condition: 20 mol; Harsh condition: 40 mol)
TABLE-US-00002 TABLE 2 Condition pH @ Mg - Gelatin pH @ Gelatin - Agar Citric Acid Added 3 3 Control (No Citric Acid) 9.5~10 8
[0114] As shown in Table 2, analysis of the model in which the operation of the ion patch was implemented revealed that, in the ion patch containing a gel with added citric acid, the pH value was consistently measured as 3 regardless of the measurement site. However, in the case without citric acid, the pH value varied by measurement site, being measured as 8 or as high as 9.5 to 10.
[0115] From this, it can be concluded that the addition of citric acid effectively suppresses the increase in pH value.
Example 4: Optimization of Current Density to Maximize Drug Absorption Rate
[0116] To enhance the absorption efficiency of the drug loaded in the provided gel, the current density applied to the ion patch was adjusted. Specifically, caffeine was added to the gelatin gel laminated on the anode of the ion patch, and various current densities of 50, 100, and 150 A were applied. The amount of caffeine absorbed into the skin was then measured and compared.
[0117] As shown in FIGS. 6a and 6b, the amount of caffeine absorbed was highest in the order of 150, 50, and 100 A current densities. In particular, the highest absorption rate was observed at 150 A, suggesting that this current density is the most suitable for application in the ion patch.
Example 5: Comparison of Drug Absorption Rate Depending on Application of Iontophoresis
[0118] To compare the difference in drug absorption rate depending on whether iontophoresis is applied, the amount of drug absorbed into human skin and reaching internal tissue was measured at 5 mm and 10 mm depths from the skin surface after applying the ion patch.
[0119] As shown in FIGS. 7a and 7b, even at the 5 mm depth, the ion patch showed significantly higher drug absorption compared to the control. Notably, at the 10 mm depth, almost no drug absorption was detected from the control group, while a measurable amount of drug was absorbed from the ion patch. From these results, it was confirmed that the application of iontophoresis enhances not only the absorption rate but also the penetration depth of the drug into the skin.
[0120] Subsequently, the skin absorption of active ingredients was examined using a skin-whitening ion patch comprising a gel containing niacinamide and an anti-aging ion patch comprising a gel containing adenosine.
[0121] As shown in FIGS. 8a and 8b, the application of iontophoresis resulted in a significantly higher absorption amount of the active ingredients compared to the control group.
Example 7: Optimization of Gel Structure and Composition
7-1. Ion Absorption Control Via Dual-Gel Structure
[0122] In constructing the ion patch operation model, two configurations were prepared as shown in FIG. 9a: one using a gelatin gel alone, and the other using a dual-gel structure by adding an agar gel to the gelatin gel.
[0123] As shown in FIG. 9b, the dual-gel model with added agar showed slower ion absorption and reduced current intensity. Therefore, this configuration allows for the adjustment of drug absorption according to specific needs.
7-2. Ion Absorption Control Depending on Gel Material
[0124] The effect of replacing the gelatin gel with alginate in the electrode structure was also compared. As shown in FIGS. 10a and 10b, compared to the use of gelatin gel, alginate gel resulted in increased ion diffusion and higher current intensity, confirming that the type of gel material significantly affects ion transport behavior.
7-3. Ion Absorption Control Depending on Electrode Selection
[0125] An analysis was conducted to determine how the absorption of active ingredients into the skin differs depending on which electrodecathode or anodethe drug-loaded gel is laminated onto.
[0126] Specifically, electrolyte gels composed of gelatin or alginate were applied to either the cathode or anode, and the amount of absorbed ions was measured.
[0127] As shown in FIGS. 11a and 11b, the alginate gel maintained a stable current of 200 A for two hours. Particularly, when used on the cathode, it showed a much higher ion absorption amount compared not only to the passive control but also to the case when applied on the anode. On the other hand, the gelatin gel, which was limited to 50 A for only one hour, showed negligible ion absorption compared to alginate.
[0128] This result suggests that the superior diffusivity of alginate enhances iontophoretic delivery efficiency.
[0129] Next, as shown in FIG. 12a, drug penetration into skin at different depths (0-1 mm, 2-3 mm, and 4-5 mm) was measured and compared according to the type of electrode laminated with the drug-loaded gel.
[0130] As shown in FIG. 12b, the overall amount of drug absorbed from the gel into the skin surface was similar for both the cathode and the anode. However, at a depth of 5 mm, only the ions delivered from the gel laminated on the cathode were detected.
[0131] As a result, a biodegradable ion patch as shown in FIG. 13 was developed.
