Drug-loaded conductive gel, its preparation method and its application in iontophoresis
A three-dimensional porous network aerogel was prepared by freezing-thawing method and combined with conductive filler to solve the problems of insufficient conductivity and drug loading of PVA gel, thus achieving a highly efficient drug delivery effect.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI NINTH PEOPLES HOSPITAL SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
- Filing Date
- 2023-05-25
- Publication Date
- 2026-07-31
AI Technical Summary
The poor conductivity and limited drug loading capacity of existing PVA gels restrict their application in iontophoresis technology.
A three-dimensional porous network aerogel was prepared by freezing-thawing and then immersed in a drug solution. The conductivity and drug loading of the gel were improved by combining it with conductive fillers such as PEDOT:PSS, polypyrrole, carbon nanotubes, and graphene.
The prepared drug-loaded conductive gel has good conductivity and high drug loading capacity, making it suitable as a drug reservoir for iontophoresis technology, thus achieving efficient transdermal drug delivery.
Smart Images
Figure CN116570553B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedicine and relates to polymer materials technology, specifically to a method for preparing a drug-loaded conductive gel and its application in iontophoresis technology. Background Technology
[0002] Iontophoresis is a biophysical method that uses direct current to deliver drug ions via electrodes into the skin, mucous membranes, or wounds, allowing them to enter local tissues or the bloodstream. It is a transdermal drug delivery technology with broad application prospects. This technology applies a low-intensity current to the skin through an iontophoresis device, pushing drug molecules into the skin. This helps enhance the transdermal delivery of charged or neutral drug molecules (uncharged neutral drug molecules, under the influence of an electric field, increase water penetration and skin hydration, rather than the direct effect of the current)
[0003] An iontophoresis device typically consists of four parts: a power supply, a control circuit, electrodes, and drug reservoirs. The power supply controls the opening and closing of the conductive pathways between the anode and cathode electrodes and the skin via the control circuit. Each electrode is connected to a drug reservoir (one containing a small or large molecule drug, and the other containing a physiologically compatible salt, such as NaCl). During iontophoresis, the drug reservoirs exchange ions with the skin to maintain the charge neutrality of both reservoirs. In operation, both reservoirs are in contact with the skin. The anode electrode and its connected reservoir deliver positively charged fentanyl ions into the body (using fentanyl as an example); the cathode electrode and its connected reservoir form a closed circuit. During drug administration, to maintain charge neutrality within the anode and cathode reservoirs, cations and anions exchange with the body, thereby delivering fentanyl cations to the skin and extracting chloride and sodium ions from the body.
[0004] Drug reservoirs are typically in patch form. Hydrogels are highly effective for drug delivery, enabling drug loading and release, and possess excellent biocompatibility and adhesion. Currently, gels are primarily used as drug reservoirs in iontophoresis devices. For example, PVA gel is well-suited as a model hydrogel for iontophoresis research; however, its poor conductivity and limited drug loading capacity present several challenges in its application.
[0005] Therefore, it is indeed necessary to develop a conductive gel with good conductivity and high drug loading capacity. Summary of the Invention
[0006] The purpose of this invention is to improve the conductivity and drug loading capacity of the gel.
[0007] To achieve the above objectives, the present invention provides a method for preparing a drug-loaded conductive gel, the method comprising:
[0008] Step 1: Mix polyvinyl alcohol with deionized water to obtain clear solution A;
[0009] Step 2: Mix the conductive filler with deionized water to obtain a homogeneous solution B;
[0010] Step 3: Mix liquid A with liquid B to obtain a homogeneous liquid C;
[0011] Step 4: Perform the freeze-thaw process on liquid C several times to obtain a gel;
[0012] Step 5: Freeze-dry the gel to obtain an aerogel;
[0013] Step 6: Immerse the aerogel in a drug solution to be loaded with drug to obtain a drug-loaded conductive gel, wherein the drug solution contains a small molecule drug solution and / or a large molecule drug solution.
[0014] Optionally, the polyvinyl alcohol is a medium-polymerization polyvinyl alcohol with a molecular weight of 120,000 to 150,000.
[0015] Optionally, in solution A, the concentration of polyvinyl alcohol is 10% (w / v) to 15% (w / v); in solution B, the mass fraction of conductive filler is 1 wt% to 5 wt%; in step 3, the volume ratio of solution A to solution B is 2:1 to 1:2.
[0016] Optionally, the conductive filler is any one or any combination of two or more of PEDOT:PSS, polypyrrole, carbon nanotubes, and graphene.
[0017] Optionally, step 4 includes 2-10 freezing-thawing processes; during the freezing-thawing process, the freezing temperature is -30 to -20°C, the freezing time is 20-30 hours, the thawing temperature is 4°C to 6°C, and the thawing time is 3-5 hours.
[0018] Optionally, in step 5, the freeze-drying temperature is -80 to -50°C, and the time is 72-96 hours.
[0019] Optionally, in step 5, pre-freezing is performed before freeze drying at a temperature of -30 to -20°C for 20-30 hours.
[0020] Optionally, the small molecule drug solution contains fentanyl and sumatriptan; the large molecule drug solution contains insulin and growth hormone; and the aerogel is soaked in the drug solution for 48-72 hours.
[0021] The present invention also provides a drug-loaded conductive gel, which is prepared by the above-described preparation method.
[0022] The present invention also provides an application of the above-mentioned drug-loaded conductive gel in iontophoresis technology, wherein the drug-loaded conductive gel serves as a drug reservoir required for iontophoresis technology and is used for transdermal drug delivery.
[0023] Compared with the prior art, the beneficial effects of the present invention include at least the following:
[0024] This invention induces gelation through a freeze-thaw process to form a three-dimensional porous network aerogel, thereby improving the gel's conductivity. The swelling process of the aerogel further enhances drug loading capacity, and the process is safe and non-toxic. The three-dimensional porous network structure of the aerogel improves both drug loading and conductivity; the prepared drug-loaded conductive gel exhibits excellent conductivity and high drug loading capacity, making it highly suitable as a drug reservoir for iontophoresis technology and showing great promise for transdermal drug delivery.
[0025] Furthermore, the preparation process of the drug-loaded conductive gel of this invention is safe, simple, and low-cost, and does not introduce small molecule toxic substances, ensuring biocompatibility. The porosity and pore size of the three-dimensional porous network structure can also be adjusted by changing the number of freeze-thaw cycles, thereby altering the gel's conductivity and swelling properties (drug loading). Attached Figure Description
[0026] Figure 1 Photographs of the drug-loaded conductive gels prepared in Examples 1-3.
[0027] Figure 2 Scanning electron microscope images of the aerogels prepared in Examples 1-3.
[0028] Figure 3 The bar graph shows the conductivity properties of the conductive gels prepared in Examples 1-3.
[0029] Figure 4 This is a diagram demonstrating the conductivity of the conductive gel prepared in Example 3.
[0030] Figure 5 The bar graph shows the compression modulus of the conductive gels prepared in Examples 1-3.
[0031] Figure 6 Line graphs comparing the drug loading capacity (swelling kinetics) of the conductive gels prepared in Examples 1-3. Detailed Implementation
[0032] In iontophoresis technology, the principle of direct current iontophoresis is based on the repulsion of like charges and the attraction of opposite charges within a direct current electric field. Drug ions are introduced into the human body through intact skin or mucous membranes. Ions with different charges can be introduced into the body; cations are introduced from the anode, and anions from the cathode. The better the conductivity of the drug reservoir in the iontophoresis device, the higher the iontophoresis efficiency, the greater the drug loading capacity, and the higher the efficiency of transdermal drug delivery.
[0033] Therefore, this invention prepares an aerogel with a three-dimensional porous network structure as a drug carrier. This aerogel swells upon immersion in a drug solution to be loaded, achieving a high drug loading capacity. By adding conductive fillers to improve conductivity, the aerogel, after loading the drug through swelling, also allows drug ions to act as charge carriers, further enhancing conductivity.
[0034] The method for preparing drug-loaded conductive gel provided by this invention includes:
[0035] Step 1: Mix polyvinyl alcohol with deionized water to obtain clear solution A.
[0036] In some embodiments, polyvinyl alcohol is slowly added to deionized water while stirring. The mixture is first cold-stirred for 15 minutes, and then heated to 95°C while stirring at 200 rpm until the solution becomes clear and transparent, thus obtaining solution A.
[0037] Generally, as the degree of polymerization increases, the viscosity of the aqueous solution increases, and the strength and solvent resistance of the film after formation improve, but the solubility in water and the elongation after film formation decrease. The polyvinyl alcohol used in this invention is a medium-degree-of-polymerization polyvinyl alcohol with a molecular weight of 120,000 to 150,000.
[0038] Step 2: Mix the conductive filler with deionized water to obtain a clear solution B.
[0039] The conductive filler is used to improve the conductivity of the gel and can be any one or any combination of two or more of PEDOT:PSS, polypyrrole, carbon nanotubes, and graphene. Since PEDOT:PSS and polypyrrole have good biocompatibility and high conductivity, and carbon nanotubes and graphene have high conductivity, in some embodiments, PEDOT:PSS or polypyrrole can also be mixed with carbon nanotubes or graphene as needed.
[0040] The Chinese name of PEDOT:PSS described in this invention is poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate), and the CAS number is 155090-83-8.
[0041] Step 3: Mix liquid A with liquid B to obtain clear liquid C.
[0042] To obtain a three-dimensional porous network structure aerogel, the polyvinyl alcohol concentration in liquid A is 10% (w / v)-15% (w / v); the conductive filler in liquid B accounts for 1wt%-5wt% by mass; in step 3, the volume ratio of liquid A to liquid B is 2:1 to 1:2, and in some embodiments, the volume ratio of liquid A to liquid B is 1:1.
[0043] Step 4: Perform the freeze-thaw process on liquid C several times to obtain a gel.
[0044] In some embodiments, this step may include 2-10 freeze-thaw cycles. The number of cycles is related to conductivity and drug loading. The porosity and pore size of the three-dimensional porous network structure can be adjusted by controlling the number of freeze-thaw cycles, thereby changing the conductivity and swelling properties (drug loading) of the gel.
[0045] During the freezing-thawing process, the freezing temperature is -30 to -20℃, the freezing time is 20-30 hours, the thawing temperature is 4℃-6℃, and the thawing time is 3-5 hours.
[0046] Step 5: Freeze-dry the gel to obtain an aerogel.
[0047] The gel can be freeze-dried within a temperature range of -80 to -50°C. Temperatures below this range may increase drying time and energy consumption. In this example, the freeze-drying temperature is -65°C, and the time is 72-96 hours. After the freeze-thaw cycle is complete, the aerogel is obtained through freeze-drying. This method is simple and efficient, and the resulting aerogel has a standardized three-dimensional porous network structure.
[0048] In some embodiments, pre-freezing is performed before freeze-drying at a temperature of -30 to -20°C for 20-30 hours. The purpose of pre-freezing is to convert the water in the hydrogel into solid ice before proceeding with the subsequent freeze-drying process.
[0049] Step 6: Immerse the aerogel in a drug solution to be loaded with drug to obtain a drug-loaded conductive gel, wherein the drug solution contains a small molecule drug solution and / or a large molecule drug solution.
[0050] The small molecule drug solution contains fentanyl, sumatriptan, etc.; the large molecule drug solution contains insulin, growth hormone, etc.
[0051] The aerogel is immersed in the drug solution for 48-72 hours. Immersing the aerogel in the drug solution utilizes the swelling behavior of the gel to load the drug. This drug loading process is safe and non-toxic, does not introduce small molecule toxic substances, and is simple and easy to operate.
[0052] Because the obtained drug-loaded conductive gel has good conductivity and high drug loading capacity, the drug-loaded conductive gel of the present invention can be used in iontophoresis technology, whereby the drug-loaded conductive gel serves as a drug reservoir required for iontophoresis technology and is administered transdermally.
[0053] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0054] Example 1
[0055] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 95 ℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0056] Add 0.2g PEDOT:PSS to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0057] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0058] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process involved one freeze-thaw cycle. The resulting gel was then frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0059] Weigh 0.001 g of fentanyl, add it to 20 mL of deionized water, and stir until dissolved to obtain a drug solution. Then, immerse the aforementioned aerogel in this drug solution for 72 hours to obtain a drug-loaded conductive gel. Figure 1 As shown, it is black and has good gel formation.
[0060] Example 2
[0061] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 90℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0062] Add 0.2g PEDOT:PSS to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0063] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0064] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process constitutes one freeze-thaw cycle. After completing two freeze-thaw cycles, the resulting gel was frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0065] Weigh 0.001 g of fentanyl, add it to 20 mL of deionized water, and stir to dissolve it evenly to obtain a drug solution. Then, soak the aforementioned aerogel in this drug solution for 72 hours to obtain a drug-loaded conductive gel. Figure 1 As shown, it is black and has good gel formation.
[0066] Example 3
[0067] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 95 ℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0068] Add 0.2g PEDOT:PSS to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0069] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0070] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process constitutes one freeze-thaw cycle. After completing three freeze-thaw cycles, the resulting gel was frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0071] Weigh 0.001 g of fentanyl, add it to 20 mL of deionized water, and stir to dissolve it evenly to obtain a drug solution. Then, soak the aforementioned aerogel in this drug solution for 72 hours to obtain a drug-loaded conductive gel. Figure 1 As shown, it is black and has good gel formation.
[0072] Scanning electron micrographs of the aerogels prepared in Examples 1-3 are shown below. Figure 2 As shown, the three-dimensional porous network structure of the gel is illustrated.
[0073] The conductivity of the conductive gels (unloaded with drug) prepared in Examples 1-3 is as follows: Figure 3As shown, the gel conductivity increases with the number of freeze-thaw cycles, reaching 0.72 S / m after three freeze-thaw cycles (Example 3). The conductivity of the conductive gel prepared in Example 3 is demonstrated as follows: Figure 4 As shown, when the gel is connected to the circuit as a conductor, the light bulb is successfully lit, proving that the conductive gel has good conductivity.
[0074] Conductive gels, used as drug reservoirs for transdermal iontophoresis, require specific mechanical properties (compression modulus) when applied to the skin; a higher compression modulus is better. The compression modulus properties of the conductive gels (unloaded with drug) prepared in Examples 1-3 are as follows: Figure 5 As shown, the gel compression modulus increases with the number of freeze-thaw cycles, reaching 344 kPa after three freeze-thaw cycles (Example 3).
[0075] The results of the comparison of the drug loading capacity (swelling kinetics) of the conductive gels prepared in Examples 1-3 are as follows: Figure 6 As shown, the gel swelling performance is strongest when there are two freeze-thaw cycles (Example 2), and it can hold up to 9.5 times the dry weight of the gel as drug solution.
[0076] Example 4
[0077] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 95 ℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0078] Add 0.2g of polypyrrole to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0079] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0080] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process constitutes one freeze-thaw cycle. After completing three freeze-thaw cycles, the resulting gel was frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0081] Weigh 3g of fentanyl, add it to 20mL of deionized water, stir and dissolve it evenly to obtain a drug solution, and then soak the aforementioned aerogel in the drug solution for 72h to obtain a drug-loaded conductive gel.
[0082] Example 5
[0083] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 95 ℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0084] Add 0.2g of carbon nanotubes to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0085] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0086] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process constitutes one freeze-thaw cycle. After completing three freeze-thaw cycles, the resulting gel was frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0087] Take 10 mL of insulin injection solution, add it to 20 mL of deionized water, stir and dissolve it evenly to obtain a drug solution, and then soak the aforementioned aerogel in the drug solution for 72 h to obtain a drug-loaded conductive gel.
[0088] Example 6
[0089] First, measure 10 mL of deionized water and add it to a glass bottle equipped with a stir bar. While stirring at 200 rpm, slowly add 1 g of polyvinyl alcohol. First, stir cold for 15 min, then heat to 95 ℃ while stirring at 200 rpm until the solution is clear and transparent, thus obtaining solution A.
[0090] Add 0.2g of graphene to 10mL of deionized water and stir for two hours to mix and disperse evenly to obtain solution B.
[0091] Measure 2 mL of solution A and 2 mL of solution B and add them to a glass bottle equipped with a stir bar. Stir for two hours to mix thoroughly to obtain solution C.
[0092] Liquid C was poured into a cylindrical mold and frozen at -24°C for 24 hours. After freezing, it was placed in a 4°C refrigerator for 3 hours to obtain a gel. This process constitutes one freeze-thaw cycle. After completing three freeze-thaw cycles, the resulting gel was frozen again at -24°C for 24 hours. After freezing, it was placed in a freeze dryer for freeze-drying at -65°C for 72 hours to obtain an aerogel.
[0093] Take 5 mL of growth hormone injection solution, add it to 20 mL of deionized water, stir and dissolve it evenly to obtain a drug solution, and then soak the aforementioned aerogel in the drug solution for 72 h to obtain a drug-loaded conductive gel.
[0094] In summary, this invention induces gelation through a freeze-thaw process, forming a three-dimensional porous network aerogel. When this aerogel is immersed in a drug solution, its three-dimensional porous network structure allows the drug solution to fill the entire network during swelling, causing volume expansion. Once swelling equilibrium is reached, the drug solution loading is complete, with a maximum load capacity of 9.5 times the dry weight of the gel. Furthermore, by adding conductive fillers to improve conductivity, the drug ions in the gel, after being loaded with drug through swelling, also act as charge carriers, further enhancing conductivity.
[0095] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.
Claims
1. A method for preparing a drug-loaded conductive gel, characterized by, The method includes: Step 1: Mix polyvinyl alcohol with deionized water to obtain a clear solution A, with a polyvinyl alcohol concentration of 10% w / v-15% w / v; wherein the polyvinyl alcohol is a medium degree of polymerization polyvinyl alcohol with a molecular weight of 120,000 to 150,000. Step 2: Mix the conductive filler with deionized water to obtain a uniform solution B, wherein the conductive filler accounts for 1wt%-5wt% of the mass fraction in solution B; wherein the conductive filler is any one or any combination of two or more of PEDOT:PSS, polypyrrole, carbon nanotubes and graphene. Step 3: Mix liquid A and liquid B to obtain a homogeneous liquid C, wherein the volume ratio of liquid A to liquid B is 2:1 to 1:
2. Step 4: Perform 2-10 freeze-thaw cycles on liquid C to obtain a gel. During the freeze-thaw process, the freezing temperature is -30℃ to -20℃ and the freezing time is 20-30h. The thawing temperature is 4℃ to 6℃ and the thawing time is 3-5h. Step 5: Pre-freeze the gel at a temperature of -30 to -20°C for 20-30 hours; then, freeze-dry the gel to obtain a three-dimensional porous network aerogel; wherein the freeze-drying temperature is -80 to -50°C and the time is 72-96 hours. Step 6: Immerse the aerogel in a drug solution to be loaded with drug. The aerogel swells in the drug solution, and the drug solution fills the three-dimensional porous network structure, causing the volume to expand. When the swelling equilibrium is reached, the drug loading is completed, and a drug-loaded conductive gel is obtained. The drug solution contains small molecule drug solution and / or large molecule drug solution. After drug loading, the drug ions act as charge carriers to further improve the conductivity of the drug-loaded conductive gel.
2. The method for preparing the drug-loaded conductive gel as described in claim 1, characterized in that, The small molecule drug solution contains fentanyl or sumatriptan; the large molecule drug solution contains insulin or growth hormone; and the aerogel is soaked in the drug solution for 48-72 hours.
3. A drug-loaded conductive gel, characterized in that, It is prepared by the preparation method described in claim 1 or 2.
4. The use of the drug-loaded conductive gel according to claim 3 in the preparation of a drug reservoir for iontophoresis transdermal drug delivery.