TW202348272A - Device and method of importing drug into tissue based on electrochemical iontophoresis - Google Patents

Abstract

The present invention discloses a device and a method of importing drug into tissue based on electrochemical iontophoresis with generating direct current, a waveform of which has gradually changing potential pulses in a shape of step mixed with square wave, for applying electrochemical iontophoresis method. One of two electrodes electrically connects to a patch containing drugs and a power supply providing the direct current, and the other one of the electrodes electrically connects to a sample of biological tissue and the power supply to import the drugs into the sample of the tissue.

Description

Drug iontophoresis device and method thereof

The present invention relates to iontophoresis devices and methods, in particular to drug iontophoresis devices and methods that promote the penetration of drugs into biological tissue samples based on electrochemical iontophoresis.

Oral cancer ranks among the top ten causes of cancer death. Current treatments include surgery, radiation therapy, and chemotherapy. For example: Oral squamous cell carcinomas (OSCC) is a malignant tumor, accounting for more than 90% of all oral cancers. Surgical resection of the affected area is the most common treatment method. However, if the scope of resection is wider, it will easily cause damage to the patient's appearance and function, so it is often used in conjunction with chemotherapy drugs. However, most chemotherapy drugs use high doses to kill cancer cells, which can easily cause serious side effects, including nephrotoxicity, severe nausea and vomiting, bone marrow suppression, ototoxicity and neurotoxicity. The most significant and common clinical toxicity is nephrotoxicity. . Therefore, how to reduce the dose of chemotherapy drugs and reduce the degree of side effects while maintaining drug efficacy is still an urgent need for research.

One object of the present invention is to provide a drug iontophoresis device and method, which provides a direct current for implementing electrochemical iontophoresis, promotes the penetration of drugs into biological tissue samples, and preferably uses nanocarriers to overcome the solubility or stability of the drug. sexual problems, and lower the dose of the drug to minimize side effects caused by the drug.

According to one aspect of the invention, the invention discloses a drug iontophoresis device, which includes: a power supply and two electrodes. The power supply provides a direct current for implementing the electrochemical ion introduction method. The waveform of the direct current is a step-like pulse wave with a square wave pulse potential accompanied by a gradual increase or decrease in oscillation. One of the electrodes is electrically connected to a patch containing a drug and the power source, and the other electrode is electrically connected to a biological tissue sample and the power source to promote the penetration of the drug in the patch into the biological tissue sample.

According to another aspect of the present invention, the present invention discloses a drug iontophoresis method, which includes: providing a direct current for implementing the electrochemical iontophoresis method, and electrically connecting one of the two electrodes to a patch containing the drug and The power source and another electrode are electrically connected to a biological tissue sample and the power source to promote the drug of the patch to penetrate into the biological tissue sample, wherein the waveform of the DC current is a step-like pulse wave with gradual oscillation increase or oscillation. Decreased square wave pulse potential.

To further illustrate each embodiment and its advantages, the present invention provides the following description in conjunction with the drawings. These drawings are part of the disclosure of the present invention. They are mainly used to illustrate the embodiments and can be combined with the relevant descriptions in the specification to explain the operating principles of the embodiments. With reference to these contents, a person with ordinary skill in the art will be able to understand other possible implementations and advantages of the present invention. The components in the figures are not drawn to scale and similar component symbols are typically used to identify similar components. As disclosed herein, "embodiment", "example" and "this embodiment" do not refer specifically to a single embodiment, but may refer to examples of implementation according to different combinations of the present invention, without departing from the spirit and scope of the present invention. The vocabulary used herein is only used to illustrate specific embodiments of the principles of the invention and should not limit the invention. Therefore, "among" can include "within" and "on", "a" and "the" can include singular or plural; "borrow" can mean "from", and "if" can mean "when" or "Once" is shown in the text before and after. In addition, "and/or" may include any possible combination of related elements.

This specification discloses multiple examples of pharmaceutical iontophoresis devices and methods thereof. Please refer to Figures 1 to 3. Figure 1 shows a drug iontophoresis device according to an example of the present invention, which is suitable for applying the drug iontophoresis method shown in Figure 2. Figure 2 shows an embodiment of the present invention. A drug iontophoresis method. Figure 3 shows a schematic diagram of the waveform of a direct current according to an embodiment of the present invention. Please note that the drug iontophoresis device of this embodiment is only an example of many systems that apply the drug iontophoresis method, and the drug iontophoresis method of the present invention is not limited thereto. The drug iontophoresis device 100 includes a power supply 110 and two electrodes 120 electrically connected to the positive and negative electrodes of the power supply 110 respectively. When performing step S3 of the drug iontophoresis method, the power supply 110 of the drug iontophoresis device 100 can provide a direct current for implementing the electrochemical iontophoresis method. The waveform of this direct current is a step-like pulse wave with gradual oscillation. The square wave pulse potential increases or oscillates down, as shown in Figure 3. Depending on the electrical properties of the drug to be driven, the direct current can be positive or negative, accompanied by a corresponding square wave pulse potential that gradually increases or decreases in oscillation. This electrochemical ion introduction method can be a differential pulse method, such as differential pulse voltammetry (DPV), which calculates data based on the difference between current points. The first point is generally taken before the pulse, and the second point is taken at the current about 40 ms after the pulse. After subtraction, it is the displayed single point current value. When performing step S4 of the drug iontophoresis method, the drug iontophoresis device 100 can be used to implement the electrochemical iontophoresis method, and an electrode 120 is electrically connected to a patch 140 and the power supply 110. In this example, the power supply is connected. The electrode 120 of the positive electrode of 110 is electrically connected to the patch 140 through the platinum foil 130. This patch contains a drug, in this example cisplatin (cisplatin); the other electrode 120 is electrically connected to a biological tissue sample 150 and the power source 110, where An example is that the electrode 120 connected to the negative electrode of the power supply 110 is electrically connected to the biological tissue sample 150 through the platinum foil 130. In this example, the biological tissue sample 150 is pig skin. The patch 140 is suitable for close contact with the biological tissue sample 150. Therefore, through the aforementioned electrical connection method, the DC current of the power supply 110 can be applied between the patch 140 and the biological tissue sample 150 to promote the patch 140 to be in contact with the biological tissue sample 150. of drugs penetrated into biological tissue samples150. Before steps S3 and S4, the drug iontophoresis method may optionally additionally include steps S1 and S2, the details of which will be introduced in subsequent paragraphs.

In this embodiment, as shown in Figure 3, the DC current can be a differential pulse waveform, which can be set by multiple parameters, such as: cycle number, starting voltage value Ei, upper limit voltage value Ev, applied pulse wave number (steps), the voltage drop amplitude of each pulse wave P _H , the duration of each pulse wave maintaining the voltage value P _W , the voltage value required to apply a pulse wave S _H , and the time required to apply a pulse wave S _T and other parameters. Preferably, the number of cycles can be between 1 and 300, the starting voltage value Ei can be between -3 and 3V, and the upper limit voltage value Ev can be between -0.5 and -5V or 0.5 and 5V. The number of pulse waves is between 2 and 2000, the voltage drop amplitude P _H of each pulse wave can be between 2 and 1000 mV, and the duration of the voltage value of each pulse wave P _W can be between 50 and 100,000. mS, the voltage value S _H required to apply a pulse wave can be between 2 and 1500 mV, and the time S _T required to apply a pulse wave can be between 100 and 25000 mS. More preferably, after many experiments, it can be obtained that when the initial voltage value Ei is between -0.5~-2V, the upper limit voltage value Ev can be between -0.5~-5V, and the number of cycles is between 5~75 between, and the power supply continues to provide DC current to the electrode 120 for 0.5 to 4 hours; or when the starting voltage value Ei is between 0.5~2V, the upper limit voltage value Ev can be between 0.5~5V, and the power supply continues Direct current is provided to the electrode 120 for 0.5 to 4 hours; in this way, a better introduction effect can be obtained, such as allowing a drug of 5 to 7 μg/mL to penetrate into the biological tissue sample 150 .

As shown in FIG. 5 , each experimental group (labeled with differential pulse voltammetry (DPV) group) and each control group (labeled with passive penetration) are used to implement the electrochemical iontophoresis method according to the drug iontophoresis method with the drug iontophoresis device 100 . The experimental results of the drug concentration of biological tissue samples in the group/chronoamperometric group/variable current group), among which the parameter settings of the nine experimental groups please refer to the table shown in Figure 6. The control group - the chronopotentiometry (CP) group was divided into three groups, namely, 0.75 mA for two hours, 1.5 mA for two hours, and 3 mA for two hours. The CP group only shows the best group in Figure 5: the experimental results of the control group-chronoamperometric group with 1.5 mA applied for two hours. In the control group - the passive penetration group, no current is applied, magnets are only placed on both sides of the patch 140 and the biological tissue sample 150, and the mixture is stirred at 500 rpm for two hours.

In order to understand whether reducing _PH can help conduct electricity, a DPV 10 cycle, _PH /2, 2h (variable voltage group) group was designed. The _PH was halved, but the results showed no significant difference. In order to understand the impact of voltage fluctuations, Ei was set to 0V, and the DPV 10 cycle, P _H /2, 2h (fluctuating voltage group) group was compared with the DPV 10 cycles, 2h (fluctuating voltage group) group, and the biological tissue of the experimental results After testing the drug content in sample 150, it was found that the drug content percentage did increase. Obviously, avoiding reverse voltage output helps to electrically introduce drugs. In order to understand the impact of increasing the voltage application time on the efficiency of electricity introduction, the ratio of voltage application and rest during the DPV action of other groups was designed, that is: the on/off ratio is 1:1, different DPVs 10 cycles, on/off = 3:1, 2h (variable voltage group) group, the on/off ratio is 3:1, and no significant difference is found. In order to understand whether providing Ei is helpful for electricity introduction, DPV 18 cycles, Ei = 0 V, 2h (varying voltage group), DPV 34 cycles, Ei = 1.0 V, 2h (varying voltage group) and DPV 63 cycles, Ei were designed. = 1.5 V, 2h (varying voltage group) three groups, it was found that as the Ei value increased, the drug content in the biological tissue sample 150 increased significantly. Therefore, it is better to adjust the setting of Ei to obtain better drug electrointroduction effect.

As shown in Figure 5, in the last experimental group, a drug iontophoresis method was implemented through a drug iontophoresis device, with the cycle number being 63 times and the starting voltage value Ei being 1.5V, so that the power supply could continuously provide DC current. Two hours after reaching the electrode 120 , the best introduction effect of this embodiment can be obtained: the drug of 6.74±0.18 μg/mL can be penetrated into the biological tissue sample 150 .

Here is an introduction to the optional additional step S1 of the drug iontophoresis method: In the following example, the nanocarrier is chitosan, the drug is cisplatin, and the coating molecule is sodium tripolyphosphate. However, the invention is not limited to this. Chitosan/cisplatin nanoparticles were prepared, using cisplatin as the drug and coating it in chitosan nanocarriers. Chitosan/cisplatin nanoparticles can be 1~1000 nm in size, and their structure can better retain the drug inside and slowly release the drug, which is suitable for drug delivery applications and can overcome the solubility or stability of the drug. problem, minimizing side effects caused by medications. Chitosan is prepared by deacetylation of chitin. The reason why chitosan is chosen as the nanocarrier here is that chitin is the second most abundant natural biopolymer, is easy to obtain, and is almost Butyrosan has good biocompatibility, degradability, low cytotoxicity, and is positively charged. Since the electrochemical iontophoresis method needs to enhance the delivery of drugs to biological tissues through electrical repulsion and electroosmosis, and biological tissues are negatively charged, chitosan has cation permeability to promote the introduction of drugs into biological tissues to reduce the dose of the drug. When the biological tissue is cancer tissue, such as oral cancer tissue, good drug introduction can be expected to reduce the lesion area and improve the specificity of the drug to the cancer tissue.

In step S1, sodium tripolyphosphate (TPP for short) is used as a cross-linking agent, and the TPP solution is dropped into the chitosan solution to form a chitosan nanocarrier. The reason for using TPP here is to take advantage of its characteristic that it will dissociate into anions during the ion gelation process, allowing electrostatic interactions to be established between chitosan chains and TPP molecules to spontaneously form nanocarriers, and there is no need for Characteristics of using organic solvents. Please refer to Figure 4, which shows the coating rate of drug nanoparticles in different chitosan nanocarrier: TPP mass ratios according to one embodiment of the present invention. It can be seen that the coating rate increases with the increase of the mass ratio. There is an upward trend, with the optimal coverage rate at the mass ratio of 15:1, and the coverage rate begins to decrease at the mass ratio of 20:1. However, considering the drug release effect, the group with a mass ratio of 15:1 released the drug at a concentration of 0.009 mg/mL within 24 hours, accounting for approximately 26.16% of the drug amount coated in the drug nanoparticles, and by the 35th Within days, 100% of the final drug dose was released, and the final release concentration reached 0.033 mg/mL, which was the best among the four groups. Therefore, preferably, the chitosan nanocarrier:TPP mass ratio can be adjusted to obtain better drug coating rate and drug release effect. The chitosan nanocarrier:TPP mass of the experimental group provided here The ratio is 15:1.

The detailed steps for preparing chitosan/cisplatin nanoparticles are: 1. Prepare 1% acetic acid to dissolve chitosan; 2. Prepare a 1.5 mg/mL chitosan solution with 1% acetic acid, and filter out impurities with a 0.22 μm filter material; 3. Use deionized water to prepare a cisplatin solution with a concentration of 1.25 mg/mL; 4. Prepare 0.5 mg/mL TPP solution with deionized water, and use filter material to filter out impurities; 5. Add 4 mL of the prepared cisplatin solution to 40 mL of chitosan solution, and stir with a magnet at 600 rpm for one minute; 6. Add 200 μL Tween80 and stir with a magnet at 600 rpm for five minutes; 7. Use an ultrasonic probe to vibrate at 6 amplitude (approximately 33W) for five minutes to evenly mix cisplatin and chitosan; 8. Use 1N NaOH to adjust the pH value of the mixed solution to 4.6~4.8; 9. Slowly drop 8 mL of 0.5 mg/mL TPP solution into the mixture, and stir with a magnet at 300 rpm for 30 minutes to cross-link the chitosan together to form drug nanoparticles; 10. Centrifuge the mixture at 20°C and 12,000 rpm for 60 minutes to obtain drug nanoparticles.

Herein is introduced an optional additional step S2 included in the drug iontophoresis method: mixing chitosan/cisplatin nanoparticles and thermosensitive hydrogel to form a patch 140 . Thermosensitive hydrogels are suitable as injectable drug delivery systems because they can undergo phase transition at body temperature (approximately 37°C), which can continuously release drugs in the target area and maximize drug efficacy. Since chemically cross-linked N-isopropylacrylamide (NIPAAm) discharges liquid at close to human body temperature, has good biocompatibility, and is not cytotoxic, the thermosensitive hydrogel used here is NIPAAm, which has a lower critical solution temperature or transition temperature of approximately 32°C. 1.358 g Poly(N-isopropylacrylamide) can be added to 20 mL of deionized water, stir until fully dissolved, then add 0.0264 g ammonium persulfate (APS), and stir until fully dissolved to prepare thermosensitive hydrogel that can undergo phase transition at 32°C. Glue.

From the above, it can be known that the drug iontophoresis device and method of the present invention provide a direct current for implementing the electrochemical iontophoresis method, thereby promoting the penetration of drugs into biological tissue samples, and preferably using nanocarriers to overcome the problem of drugs. solubility or stability issues and reduce the dose of the drug to minimize side effects caused by the drug.

The above description is based on a number of different embodiments of the present invention, in which various features can be implemented singly or in different combinations. Therefore, the disclosed embodiments of the present invention are specific examples to illustrate the principles of the present invention, and should not be limited to the disclosed embodiments of the present invention. Furthermore, the previous description and the accompanying drawings are only for demonstration of the present invention and are not limited thereto. Changes or combinations of other elements are possible without departing from the spirit and scope of the invention.

100: Drug iontophoresis device 110:Power supply 120:Electrode 130:Platinum foil 140: patch 150:Biological tissue samples S1, S2, S3, S4: steps

FIG. 1 shows a drug iontophoresis device according to an example of the present invention, which is suitable for applying the drug iontophoresis method shown in FIG. 2 .

Figure 2 shows a drug iontophoresis method according to an embodiment of the present invention.

FIG. 3 shows a schematic diagram of a DC current waveform according to an embodiment of the present invention.

Figure 4 shows the coating rates of drug nanoparticles in different nanocarrier:coating molecule mass ratios according to one embodiment of the present invention.

Figure 5 shows the experimental results of drug concentrations in biological tissue samples in each experimental group and control group.

Figure 6 shows the parameter settings of each experimental group in Figure 5.

100: Drug iontophoresis device

110:Power supply

120:Electrode

130:Platinum foil

140: patch

150:Biological tissue samples

Claims (12)

A drug iontophoresis device, including: A power supply that provides a direct current for implementing the electrochemical iontophoresis method. The waveform of the direct current is a step-like pulse wave and a square wave pulse potential accompanied by a gradual increase in oscillation or a decrease in oscillation; and Two electrodes, one electrode is electrically connected to a patch and the power source, the patch contains medicine, and the other electrode is electrically connected to a biological tissue sample and the power source to promote the drug in the patch to penetrate into the biological tissue sample. The drug iontophoresis device as described in claim 1, wherein the direct current is set based on parameters of the initial voltage value Ei, and the initial voltage value Ei is between -3~3V. The drug iontophoresis device as described in claim 2, wherein the parameter setting of the DC current further includes the number of cycles and the upper limit voltage value Ev. When the initial voltage value Ei is between 0.5~2V, the number of cycles is between 0.5 and 2V. Between 1~300, the upper limit voltage value Ev is between 0.5~5V, and the power supply continues to provide the DC current to the electrodes for 0.5~4 hours; when the initial voltage value Ei is between -0.5~- When 2V, the number of cycles is between 1 and 300, the upper limit voltage value Ev is between -0.5 and -5V, and the power supply continues to provide the DC current to the electrodes for 0.5 to 4 hours. The drug iontophoresis device according to claim 2, wherein the parameters for setting the DC current also include the number of applied pulse waves, the amplitude of the voltage drop of each pulse wave P _H , and the duration P of the voltage value of each pulse wave. _W , the voltage value S _H required to apply a pulse wave, the time required to apply a pulse wave S _T , the number of applied pulse waves is between 2-2000, and the voltage drop amplitude _PH of each pulse wave is between Between 2~1000 mV, the duration P _W of each pulse wave maintaining voltage value is between 50~100000 mS, the voltage value S _H required to apply a pulse wave is between 2~1500 mV, and The time S _T required to apply a pulse wave is between 100 and 25000 mS. The drug iontophoresis device as described in claim 1, wherein the example nanocarrier is chitosan, the coating molecule is sodium tripolyphosphate, the drug is cisplatin, and the drug is coated in Drug nanoparticles are formed in the nanocarrier and mixed with the temperature-sensitive hydrogel to form the patch. As for the drug iontophoresis device described in claim 5, one of the two electrodes is electrically connected to a patch containing the drug and the power source, and the other electrode is electrically connected to a biological tissue sample and the power source to promote the The patch penetrates the biological tissue sample with 5~7 μg/mL of the drug. A drug iontophoresis method, including: Provide a direct current for implementing electrochemical iontophoresis, and one of the two electrodes is electrically connected to a patch containing medicine and the power source, and the other electrode is electrically connected to a biological tissue sample and the power source to cause the patch to The drug is distributed and penetrates into the biological tissue sample, The waveform of the DC current is a step-like pulse wave with a square wave pulse potential accompanied by a gradual increase or decrease in oscillation. The drug iontophoresis method described in claim 7 further includes: setting the direct current with a parameter of an initial voltage value Ei, and the initial voltage value Ei is between -3~3V. The drug iontophoresis method described in claim 8 further includes: setting the DC current with the parameters of the number of cycles and the upper limit voltage value Ev, so that when the initial voltage value Ei is between 0.5 and 2V, the The number of cycles is between 1 and 300, the upper limit voltage value Ev is between 0.5 and 5V, and the power supply continues to provide the DC current to the electrodes for 0.5 to 4 hours; and when the initial voltage value Ei is between When it is between -0.5~-2V, the number of cycles is between 1~300, the upper limit voltage value Ev is between -0.5~-5V, and the power supply continues to provide the DC current to the electrodes 0.5~ 4 hours. The drug iontophoresis method as described in claim 8, further comprising: applying a pulse wave number, a voltage drop amplitude P _H of each pulse wave, a duration P _W of maintaining the voltage value of each pulse wave, and applying a The parameters of the required voltage value of the pulse wave S _H and the time required to apply a pulse wave S _T set the DC current. The number of applied pulse waves is between 2 and 2000. The voltage value of each pulse wave decreases by P _H Between 2 and 1000 mV, the duration of each pulse wave maintaining voltage value P _W is between 50 and 100000 mS, and the voltage value S _H required to apply a pulse wave is between 2 and 1500 mV. , and the time S _T required to apply a pulse wave is between 100 and 25000 mS. The drug iontophoresis method as described in claim 7, which further includes: using chitosan as a nanocarrier, sodium tripolyphosphate as a coating molecule, and cisplatin (cisplatin) as an example of the drug. The drug nanoparticles are coated in the nanocarrier and mixed with the temperature-sensitive hydrogel to form the patch. The drug iontophoresis method as described in claim 11, wherein one of the two electrodes is electrically connected to a patch containing the drug and the power source, and the other electrode is electrically connected to a biological tissue sample and the power source to promote The drug of the patch penetrates into the biological tissue sample at 5~7 μg/mL.

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