Preparation method of drug carrier combined with ultrasonic transdermal drug delivery

Abstract

The invention provides a preparation method of a drug carrier combined with ultrasonic transdermal drug delivery, according to the method, a micro-fluidic chip is used, an oil phase solution and a water phase solution can be accurately treated under a micro-scale through a micro-fluidic technology, drug carriers with different particle sizes are prepared, the particle sizes are uniform and controllable, and the repeatability is good. The drug carrier disclosed by the invention can be combined with ultrasound to realize accurate transdermal drug delivery, and under the action of the ultrasound, according to the obvious difference of the drug carriers with different characteristics in rupture time and acting force, the delivery sequence, depth and structural layer of the content of the drug carrier are accurately adjusted, so that the controllable release and accurate delivery of the drug are realized.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing a pharmaceutical carrier for combined ultrasonic transdermal administration. Background Art

[0002] Transdermal drug delivery (TDD) is a method of delivering an effective amount of a drug through the patient's skin to the body to achieve local or systemic treatment. Compared with other drug delivery methods, TDD has the advantages of external use, first-pass metabolism avoidance, rapid and effective treatment to accelerate wound healing, and minimal toxicity to non-target tissues. However, for now, TDD has been limited by the tough and lipid-rich outer layer of the skin (called the stratum corneum (SC)), which makes it impossible for most biological drugs to penetrate the skin. At present, a variety of active (such as iontophoresis, electroporation, laser, ultrasound, microneedles, etc.) and / or passive (drug carriers: liposomes, transfersomes, polymer nanoparticles, nanolotions, etc.) transdermal drug delivery methods have been proposed to break through the SC. Due to the presence of the stratum corneum or necrotic tissue barrier, it is difficult for drugs to be transferred to deeper target areas. Some diseases require simultaneous targeting of the skin and subcutaneous tissue, and drugs with similar molecular weights need to be delivered to different structural layers. Therefore, high requirements are placed on the order of drug delivery, the structural layer or depth reached. At present, most transdermal drug delivery methods do not take into account the multi-layered anatomical structure inside the skin tissue, nor do they accurately control the order, number of structural layers and depth of drug delivery.

[0003] Currently, multilayer stents have been proposed to allow different therapeutic drugs to be incorporated into each layer and released locally at relevant locations, but their disadvantages include the complex drug incorporation process, possible drug loss or deformation after stent modification, and byproducts during stent degradation that may cause immunogenicity and toxicity. Microneedles of different lengths may also produce different drug delivery effects by reaching different predetermined puncture depths, but due to the invasive method, there is still potential user discomfort (possibility of irritation and infection, pain and skin damage). Therefore, it is particularly important to develop a non-invasive and precise transdermal drug delivery system that can deliver a variety of therapeutic drugs as needed to achieve higher treatment accuracy and efficiency. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing a drug carrier for transdermal drug delivery combined with ultrasound in view of the deficiencies of the above-mentioned prior art. The solution can be precisely processed at a microscale through microfluidic technology to produce a drug carrier with uniform and controllable particle size and quantitative loading. Ultrasound has the advantages of being non-invasive, reaching deep tissues and being low-cost. When combined with a drug carrier, ultrasound can serve as a trigger for drug release. By adjusting the properties and contents of the drug carrier, controlled release under ultrasound can be achieved, thereby achieving precise drug delivery.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0006] A method for preparing a drug carrier for transdermal administration combined with ultrasound, the method comprising the following steps:

[0007] S1. Solution preparation

[0008] dissolving the lipid material in an organic solvent to form a lipid solution as an oil phase;

[0009] The surfactant is mixed with a buffer or water, and sucrose is added as the internal aqueous phase;

[0010] Mixing the surfactant with glycerol, or mixing the surfactant with a buffer and then adding glycerol, as the external aqueous phase;

[0011] When the administered drug is a fat-soluble drug, it dissolves in the oil phase; when the administered drug is a water-soluble drug, it dissolves in the internal water phase;

[0012] S2. Preparation of drug carrier

[0013] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. It uses a four-channel microfluidic chip, which contains channels for ultrasound-responsive substances, inner water phase, oil phase, and outer water phase. The ultrasound-responsive substances and the inner water phase together constitute the inner phase solution.

[0014] The aqueous and oily phase solutions are pumped from different channels into a collection pool at the channel connection for mixing through a microfluidic platform. The flow rates of the solutions are controlled by different injection pumps. The prepared drug carriers are collected at the solution outlets of the microfluidic platform and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining transdermal drug carriers encapsulating ultrasound-responsive substances.

[0015] Preferably, the present invention can also use a three-channel microfluidic chip to prepare a drug carrier that does not carry an ultrasound-responsive substance, wherein the three channels are an inner water phase channel, an oil phase channel, and an outer water phase channel.

[0016] Preferably, the lipid material in S1 is one or more of phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, cholesterol or phosphatidylglycerol; the organic solvent is one or more of n-octanol, n-propanol, isopropanol, ethanol or oleic acid; the mass concentration of the lipid material in the oil phase is 0.1-10%.

[0017] Preferably, the surfactant in S1 is one or more of Pluronic F68, Pluronic F127 or tween-80; the buffer is one of sodium chloride buffer, phosphate buffer or Tris-HCl buffer;

[0018] The mass concentration of sucrose in the inner aqueous phase is 1-10%, and the volume ratio of surfactant to buffer or water is (1-2): (1-5);

[0019] The mass concentration of glycerol in the external water phase is 1-20%, and the volume ratio of the surfactant to the buffer solution is (1-2): (1-5).

[0020] Preferably, the fat-soluble drugs in S1 include drugs that inhibit inflammation (such as triamcinolone acetonide or dexamethasone, etc.), and the water-soluble drugs include drugs that inhibit inflammation (such as doxycycline, etc.) or promote angiogenesis (such as deferoxamine mesylate or growth factors, etc.).

[0021] Preferably, the microfluidic chip in S2 is composed of a glass slide and PDMS or PMMA.

[0022] Preferably, the ultrasound responsive substance in S2 is a perfluorocarbon, specifically one or more of perfluoropentane or perfluorohexane.

[0023] Preferably, the mass ratio of the inner water phase, oil phase and outer water phase solution in S2 is 1:(1-20):(10-100), and the ratio of the ultrasonic response substance to the inner water phase is 1:(5-10).

[0024] The present invention also provides a drug carrier prepared by the method.

[0025] The present invention also provides an application of the drug carrier, which can be used in combination with ultrasound to achieve precise transdermal drug delivery. Under the action of ultrasound, the drug carrier can precisely adjust the drug delivery sequence, depth and structural layer through significant differences in rupture time and force, thereby achieving precise transdermal drug delivery.

[0026] The present invention has significant technical effects due to the adoption of the above technical solution:

[0027] 1. The present invention provides a method for preparing a drug carrier for transdermal drug delivery combined with ultrasound. The solution can be precisely processed at a microscale through microfluidic technology to produce a drug carrier with uniform and controllable particle size and quantitative loading. Ultrasound has the advantages of being non-invasive, reaching deep tissues and being low-cost. When combined with a drug carrier, ultrasound can serve as a trigger for drug release. By adjusting the properties and contents of the drug carrier, controlled release under ultrasound can be achieved, thereby achieving precise drug delivery.

[0028] 2. The microfluidics-based drug carrier preparation method of the present invention can prepare drug carriers with different particle sizes, the particle size of which is controllable, and can stably produce drug carriers with a specific particle size with good repeatability.

[0029] 3. The drug carrier of the present invention can combine water-soluble drugs or fat-soluble drugs with ultrasound to achieve precise transdermal delivery. Under the action of ultrasound, drug carriers with different characteristics show significant differences in rupture time and force. The delivery order, depth and structural layer of the contents of the drug carrier can be precisely adjusted to achieve non-invasive and precise drug delivery.

[0030] The present invention is further described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a process flow chart of the preparation of a drug carrier for transdermal drug delivery combined with ultrasound based on microfluidics technology in Example 1 of the present invention;

[0032] Figure 2 is a schematic diagram of a four-channel microfluidic chip according to Example 1 of the present invention;

[0033] Figure 3 Schematic diagram of the structure of a water-soluble drug carrier encapsulating an ultrasound-responsive substance prepared in Example 1 of the present invention;

[0034] Figure 4 Schematic diagram of a three-channel microfluidic chip of Comparative Example 1 of the present invention;

[0035] Figure 5 It is a schematic structural diagram of a water-soluble drug carrier without encapsulating an ultrasound-responsive substance prepared in Comparative Example 1 of the present invention;

[0036] Figure 6 1 is a graph showing the penetration depth of fluorescent drugs in different drug carriers in Example 4 of the present invention, wherein (a) shows the penetration depth of fluorescent drugs in drug carriers without ultrasound-responsive substances after ultrasound action, and (b) shows the penetration depth of fluorescent drugs in drug carriers with ultrasound-responsive substances after ultrasound action;

[0037] Figure 7 It is a schematic diagram of the structure of the fat-soluble drug carrier encapsulating the ultrasound-responsive substance prepared in Example 5 of the present invention. DETAILED DESCRIPTION

[0038] Example 1

[0039] This embodiment is a method for preparing a drug carrier for transdermal drug administration combined with ultrasound, using a four-channel microfluidic chip, and the drug is a water-soluble drug doxycycline. The method includes the following steps:

[0040] S1. Solution preparation

[0041] Phosphatidylcholine and dipalmitoylphosphatidylethanolamine were mixed in a ratio of 1:1, dissolved in ethanol at a mass concentration of 20% (w / v) to form a lipid stock solution, and then the lipid stock solution was dissolved in n-octanol at a volume ratio of 1:1 to form an oil phase;

[0042] The nonionic surfactant F68 and the phosphate buffer solution are mixed in a volume ratio of 1:1, and then sucrose is added in a mass concentration of 1% (w / v) to form an inner aqueous phase solution, and the drug doxycycline is dissolved in the inner aqueous phase solution;

[0043] The nonionic surfactant F68 and the phosphate buffer solution were mixed at a volume ratio of 1:1, and then glycerol was added at a mass concentration of 10% (w / v) to form an external aqueous phase solution.

[0044] S2. Preparation of drug carrier

[0045] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A four-channel microfluidic chip is used. The four channels are an inner water phase, an ultrasonic response substance channel, an oil phase, and an outer water phase channel. The ultrasonic response substance and the inner water phase together constitute the inner phase. Different solutions entering the chip channel are precisely controlled by different syringe pumps. By controlling the speed of each phase solution, different flow rate ratios are formed, thereby regulating the particle size of the drug carrier.

[0046] The constructed microfluidic platform was used to prepare a drug carrier encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:20:100, the ultrasound-responsive substance was perfluorohexane, and the ratio to the inner water phase was 1:10, and the concentration of the drug doxycycline in the total solution was 1 mg / mL. The prepared drug carrier was collected at the outlet of the microfluidic platform solution, and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0047] The preparation process of the drug carrier for transdermal drug delivery based on microfluidics combined with ultrasound is as follows: Figure 1 shown.

[0048] The schematic diagram of the four-channel microfluidic chip in this embodiment is as follows Figure 2 shown.

[0049] The schematic diagram of the structure of the drug carrier prepared in this example is as follows Figure 3 As shown, the ultrasonic responsive substance is encapsulated therein and the particles are large in size, with a particle size of 30 μm.

[0050] Comparative Example 1

[0051] A method for preparing a drug carrier that can be administered transdermally uses a three-channel microfluidic chip, and the drug is a water-soluble drug doxycycline. The method comprises the following steps:

[0052] S1. Solution preparation

[0053] Dissolve phosphatidylcholine in ethanol at a mass concentration of 20% (w / v) to form a lipid stock solution, and then dissolve the lipid stock solution in n-octanol at a volume ratio of 1:1 to form an oil phase;

[0054] The nonionic surfactant F68 and the phosphate buffer solution are mixed in a volume ratio of 1:1, and then sucrose is added in a mass concentration of 1% (w / v) to form an inner aqueous phase solution, and the drug doxycycline is dissolved in the inner aqueous phase solution;

[0055] The nonionic surfactant F68 and the phosphate buffer solution were mixed at a volume ratio of 1:1, and then glycerol was added at a mass concentration of 10% (w / v) to form an external aqueous phase solution.

[0056] S2. Preparation of drug carrier

[0057] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A three-channel microfluidic chip is used. The three channels are the inner water phase, the oil phase, and the outer water phase channels. Different solutions entering the chip channels are precisely controlled by different syringe pumps. By controlling the solution speeds of the inner and outer water phases and the oil phase, different flow rate ratios are formed, thereby regulating the particle size of the drug carrier.

[0058] The constructed microfluidic platform was used to prepare a drug carrier without encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:10:50, and the concentration of the drug doxycycline in the total solution was 1 mg / mL. The prepared drug carrier was collected at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0059] The schematic diagram of the three-channel microfluidic chip in this comparative example is as follows Figure 4 shown.

[0060] The schematic diagram of the structure of the drug carrier prepared in this comparative example is as follows Figure 5 As shown, no ultrasound responsive substance is encapsulated therein, and the particles are small in size, with a particle size of 10 μm.

[0061] Example 2

[0062] This embodiment is a method for preparing a drug carrier for transdermal drug administration combined with ultrasound, using a four-channel microfluidic chip, and the drug is a water-soluble drug doxycycline. The method includes the following steps:

[0063] S1. Solution preparation

[0064] Phosphatidylcholine and cholesterol were mixed in a ratio of 2:1 and dissolved in oleic acid at a mass concentration of 3% (w / v) to form an oil phase;

[0065] The nonionic surfactant F68 and water are mixed at a volume ratio of 1:5, and sucrose is added at a mass concentration of 10% (w / v) to form an inner aqueous phase solution, and the drug doxycycline is dissolved in the inner aqueous phase solution;

[0066] The nonionic surfactant F68 and glycerol were mixed in a volume ratio of 6:1 to form an external aqueous phase solution.

[0067] S2. Preparation of drug carrier

[0068] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PMMA. A four-channel microfluidic chip is used. The four channels are the inner water phase, the ultrasound response substance channel, the oil phase, and the outer water phase channel. The ultrasound response substance and the inner water phase together constitute the inner phase. Different solutions entering the chip channel are precisely controlled by different syringe pumps. By controlling the speed of each phase solution, different flow rate ratios are formed, thereby regulating the particle size of the liposome.

[0069] The constructed microfluidic platform was used to prepare a drug carrier encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:1:10, the ultrasound-responsive substance was perfluoropentane and perfluorohexane (1:1), and the ratio to the inner water phase was 1:5, and the concentration of the drug doxycycline in the total solution was 1 mg / mL. The prepared drug carrier was collected at the outlet of the microfluidic platform solution, and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0070] The drug carrier prepared in this embodiment encapsulates the ultrasound-responsive substance and has a large particle size of 40 μm.

[0071] Comparative Example 2

[0072] A method for preparing a drug carrier that can be administered transdermally uses a three-channel microfluidic chip, and the drug is a water-soluble drug doxycycline. The method comprises the following steps:

[0073] S1. Solution preparation

[0074] Phosphatidylcholine and cholesterol were mixed in a ratio of 2:1 and dissolved in oleic acid at a mass concentration of 3% (w / v) to form an oil phase;

[0075] The nonionic surfactant F68 and water are mixed at a volume ratio of 1:5, and sucrose is added at a mass concentration of 10% (w / v) to form an inner aqueous phase solution, and the drug doxycycline is dissolved in the inner aqueous phase solution;

[0076] The nonionic surfactant F68, tween-80 and glycerol were mixed in a volume ratio of 6:1:1 to form an external aqueous phase solution.

[0077] S2. Preparation of drug carrier

[0078] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PMMA. A three-channel microfluidic chip is used. The three channels are the inner water phase, the oil phase, and the outer water phase channels. Different solutions entering the chip channels are precisely controlled by different syringe pumps. By controlling the solution speeds of the inner and outer water phases and the oil phase, different flow rate ratios are formed, thereby regulating the particle size of the liposomes.

[0079] The constructed microfluidic platform was used to prepare a drug carrier without encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:2:25, and the concentration of the drug doxycycline in the total solution was 1 mg / mL. The prepared drug carrier was collected at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0080] The drug carrier prepared in this comparative example does not contain any ultrasound-responsive substance and has a small particle size of 20 μm.

[0081] Example 3

[0082] This embodiment is a method for preparing a drug carrier for transdermal drug delivery combined with ultrasound, using a four-channel microfluidic chip, the drug is a water-soluble drug growth factor, and the method comprises the following steps:

[0083] S1. Solution preparation

[0084] Dissolve phosphatidylcholine in ethanol at a mass concentration of 5% (w / v) to form a lipid stock solution, and then dissolve the lipid stock solution in n-octanol at a volume ratio of 1:20 to form an oil phase;

[0085] The nonionic surfactant F68 and the sodium chloride buffer solution are mixed in a volume ratio of 1:2, and then sucrose is added at a mass concentration of 8% (w / v) to form an inner aqueous phase solution, and the drug growth factor is dissolved in the inner aqueous phase solution;

[0086] The nonionic surfactant F68 and glycerol were mixed in a volume ratio of 9:1 to form an external aqueous phase solution.

[0087] S2. Preparation of drug carrier

[0088] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A four-channel microfluidic chip is used. The four channels are the inner water phase, the ultrasound response substance channel, the oil phase, and the outer water phase channel. The ultrasound response substance and the inner water phase together constitute the inner phase. Different solutions entering the chip channel are precisely controlled by different syringe pumps. By controlling the speed of each phase solution, different flow rate ratios are formed, thereby regulating the particle size of the liposome.

[0089] The constructed microfluidic platform was used to prepare a drug carrier encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:2:13, the ultrasound-responsive substance was perfluoropentane, and the ratio to the inner water phase was 1:9; the concentration of the drug growth factor in the total solution was 1 mg / mL. The drug carrier was prepared at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0090] The drug carrier prepared in this example encapsulates the ultrasound-responsive substance and has a large particle size of 30 μm.

[0091] Comparative Example 3

[0092] A method for preparing a drug carrier that can be administered transdermally, using a three-channel microfluidic chip, the drug is a water-soluble drug growth factor, the method comprises the following steps:

[0093] S1. Solution preparation

[0094] Dissolve phosphatidylcholine in ethanol at a mass concentration of 5% (w / v) to form a lipid stock solution, and then dissolve the lipid stock solution in n-octanol at a volume ratio of 1:20 to form an oil phase;

[0095] The nonionic surfactant F68 and the sodium chloride buffer solution are mixed in a volume ratio of 1:2, and then sucrose is added at a mass concentration of 8% (w / v) to form an inner aqueous phase solution, and the drug growth factor is dissolved in the inner aqueous phase solution;

[0096] The nonionic surfactant F68 and glycerol were mixed in a volume ratio of 9:1 to form an external aqueous phase solution.

[0097] S2. Preparation of drug carrier

[0098] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A three-channel microfluidic chip is used. The three channels are the inner water phase, the oil phase, and the outer water phase channels. Different solutions entering the chip channels are precisely controlled by different syringe pumps. By controlling the solution speeds of the inner and outer water phases and the oil phase, different flow rate ratios are formed, thereby regulating the particle size of the liposomes.

[0099] The constructed microfluidic platform was used to prepare a drug carrier without encapsulating ultrasound-responsive substances, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:4:25, and the concentration of the drug growth factor in the total solution was 1 mg / mL. The prepared drug carrier was collected at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0100] The drug carrier prepared in this comparative example does not contain any ultrasound-responsive substance and has a small particle size of 10 μm.

[0101] Example 4

[0102] In order to better observe the entry of drugs into the skin, calcium yellow green fluorescent drugs were used instead of the encapsulated drugs in the drug carriers. The drug carrier preparation methods of Example 3 and Comparative Example 3 were used to prepare large-particle drug carriers encapsulating ultrasound-responsive substances and small-particle drug carriers not encapsulating ultrasound-responsive substances, respectively. The resulting solutions were collected, and the generated droplets were dialyzed to filter out unencapsulated drugs and debris.

[0103] Using 3% agarose to simulate the skin, large-particle drug carriers containing ultrasound-responsive substances and small-particle drug carriers without ultrasound-responsive substances were placed on the agar block, and low-frequency, low-intensity ultrasound was used for transdermal drug delivery. At the same time, there was a significant difference in the depth of penetration of the two fluorescent drugs into the agar block. The specific results are shown in Figure 6 , where (a) shows the penetration depth of fluorescent drugs in small-sized liposomes without ultrasound-responsive substances after ultrasound, and (b) shows the penetration depth of fluorescent drugs in large-sized liposomes with ultrasound-responsive substances after ultrasound. As can be seen from the figure, liposomes encapsulating ultrasound-responsive substances can rupture and release their contents faster, and produce cavitation under ultrasound, allowing the contents to penetrate deeper, indicating that this method can achieve non-invasive and precise drug delivery.

[0104] Example 5

[0105] This embodiment is a method for preparing a drug carrier for combined ultrasound transdermal drug delivery, using a four-channel microfluidic chip, the drug is a fat-soluble drug triamcinolone acetonide, and the method comprises the following steps:

[0106] S1. Solution preparation

[0107] Dissolve phosphatidylethanolamine in ethanol at a mass concentration of 10% (w / v) to form a lipid stock solution, then dissolve the lipid stock solution in n-propanol at a volume ratio of 1:100 to form an oil phase, and dissolve the drug triamcinolone acetonide in the oil phase;

[0108] The nonionic surfactant F127 and phosphate buffer were mixed in a volume ratio of 2:5, and sucrose was added at a mass concentration of 5% (w / v) to form an inner aqueous phase solution;

[0109] The nonionic surfactant F127 and glycerol were mixed in a volume ratio of 5:1 to form an external aqueous phase solution.

[0110] S2. Preparation of drug carrier

[0111] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A four-channel microfluidic chip is used. The four channels are the inner water phase, the ultrasound response substance channel, the oil phase, and the outer water phase channel. The ultrasound response substance and the inner water phase together constitute the inner phase. Different solutions entering the chip channel are precisely controlled by different syringe pumps. By controlling the speed of each phase solution, different flow rate ratios are formed, thereby regulating the particle size of the liposome.

[0112] The constructed microfluidic platform was used to prepare a drug carrier encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:4:20, the ultrasound-responsive substance was perfluoropentane, and the ratio to the inner water phase was 1:8, and the concentration of the drug triamcinolone acetonide in the total solution was 2 mg / mL. The drug carrier was prepared at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0113] The schematic diagram of the structure of the drug carrier prepared in this example is as follows Figure 7 As shown, ultrasound responsive substances are encapsulated therein and the particle size is 20 μm.

[0114] Example 6

[0115] This embodiment is a method for preparing a drug carrier for transdermal drug administration combined with ultrasound, using a four-channel microfluidic chip, and the drug is a fat-soluble drug dexamethasone. The method comprises the following steps:

[0116] S1. Solution preparation

[0117] Dissolving phosphatidylglycerol in isopropanol at a mass concentration of 5% (w / v) to form an oil phase, and dissolving the drug dexamethasone in the oil phase;

[0118] The nonionic surfactant F68 and Tris-HCl buffer were mixed in a volume ratio of 2:3, and sucrose was added at a mass concentration of 3% (w / v) to form an inner aqueous phase solution;

[0119] The nonionic surfactant F68, tween-80 and glycerol were mixed in a volume ratio of 5:4:1 to form an external aqueous phase solution.

[0120] S2. Preparation of drug carrier

[0121] The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. The microfluidic chip is composed of a glass slide and PDMS. A four-channel microfluidic chip is used. The four channels are the inner water phase, the ultrasound response substance channel, the oil phase, and the outer water phase channel. The ultrasound response substance and the inner water phase together constitute the inner phase. Different solutions entering the chip channel are precisely controlled by different syringe pumps. By controlling the speed of each phase solution, different flow rate ratios are formed, thereby regulating the particle size of the liposome.

[0122] The constructed microfluidic platform was used to prepare a drug carrier encapsulating an ultrasound-responsive substance, wherein the mass ratio of the inner water phase, the oil phase, and the outer water phase was 1:15:80, the ultrasound-responsive substance was perfluoropentane, and the ratio to the inner water phase was 1:7, and the concentration of the drug dexamethasone in the total solution was 2 mg / mL. The drug carrier was prepared at the outlet of the microfluidic platform solution and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining a drug carrier.

[0123] The drug carrier prepared in this example encapsulates the ultrasound-responsive substance and has a particle size of 20 μm.

[0124] The present invention can accurately process solutions at a microscale through microfluidic technology to prepare ultrasound-responsive drug carriers with uniform and controllable particle size and quantitative loading. Under the action of low-frequency and low-intensity ultrasound, drug carriers with different characteristics show significant differences in rupture time and force, and the delivery order, depth and structural layer of the contents of the drug carrier can be accurately adjusted to achieve controlled release and precise delivery of drugs in a non-invasive manner.

[0125] The above is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent change made to the above embodiment according to the technical essence of the invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing a drug carrier for transdermal administration combined with ultrasound, characterized in that: The method comprises the following steps: S1. Solution preparation dissolving the lipid material in an organic solvent to form a lipid solution as an oil phase; The surfactant is mixed with a buffer or water, and sucrose is added as the internal aqueous phase; Mixing the surfactant with glycerol, or mixing the surfactant with a buffer and then adding glycerol, as the external aqueous phase; When the administered drug is a fat-soluble drug, it dissolves in the oil phase; when the administered drug is a water-soluble drug, it dissolves in the internal water phase; S2. Preparation of drug carrier The microfluidic platform consists of a microscope, a microfluidic chip, and a syringe pump. It uses a four-channel microfluidic chip, which contains channels for ultrasound-responsive substances, inner water phase, oil phase, and outer water phase. The ultrasound-responsive substances and the inner water phase together constitute the inner phase solution. The aqueous and oily phase solutions are pumped from different channels into a collection pool at the channel connection for mixing through a microfluidic platform. The flow rates of the solutions are controlled by different injection pumps. The prepared drug carriers are collected at the solution outlets of the microfluidic platform and purified by dialysis to remove unencapsulated drugs and impurities, thereby obtaining transdermal drug carriers encapsulating ultrasound-responsive substances.

2. The method according to claim 1, characterized in that A three-channel microfluidic chip can also be used to prepare a drug carrier that does not carry an ultrasound-responsive substance, wherein the three channels are an inner water phase channel, an oil phase channel, and an outer water phase channel.

3. The method according to claim 1 or 2, characterized in that: The lipid material in S1 is one or more of phosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, cholesterol or phosphatidylglycerol; the organic solvent is one or more of n-octanol, n-propanol, isopropanol, ethanol or oleic acid; the mass concentration of the lipid material in the oil phase is 0.1-10%.

4. The method according to claim 1 or 2, characterized in that: The surfactant in S1 is one or more of Pluronic F68, Pluronic F127 or tween-80; the buffer is one of sodium chloride buffer, phosphate buffer or Tris-HCl buffer; The mass concentration of sucrose in the inner aqueous phase is 1-10%, and the volume ratio of surfactant to buffer or water is (1-2): (1-5); The mass concentration of glycerol in the external water phase is 1-20%, and the volume ratio of the surfactant to the buffer solution is (1-2): (1-5).

5. The method according to claim 1 or 2, characterized in that: The microfluidic chip described in S2 is composed of a glass slide and PDMS or PMMA.

6. The method according to claim 1 or 2, characterized in that: The ultrasound responsive substance in S2 is a perfluorocarbon, specifically one or more of perfluoropentane or perfluorohexane.

7. The method according to claim 1 or 2, characterized in that: The mass ratio of the inner water phase, oil phase and outer water phase solution in S2 is 1:(1-20):(10-100), and the ratio of the ultrasonic response substance to the inner water phase is 1:(5-10).

8. A drug carrier prepared by the method according to any one of claims 1 to 7.

9. Use of the drug carrier according to claim 8, characterized in that: The drug carrier can be combined with ultrasound to achieve precise transdermal drug delivery.

10. The use according to claim 9, characterized in that: Under the action of ultrasound, the drug delivery sequence, depth and structural layer are precisely adjusted through significant differences in the rupture time and force of the drug carriers to achieve precise transdermal delivery.

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