Low-temperature photo-thermal phase change material for assisting transdermal drug delivery, low-temperature photo-thermal transdermal drug delivery material and preparation method of low-temperature photo-thermal phase change material

Abstract

The invention belongs to the technical field of transdermal drug delivery, and particularly relates to a low-temperature photo-thermal phase change material for assisting transdermal drug delivery, a low-temperature photo-thermal transdermal drug delivery material and a method. The low-temperature photo-thermal transdermal drug delivery material comprises a low-temperature photo-thermal phase-change material and a drug to be delivered, wherein the low-temperature photo-thermal phase-change material comprises a phase-change material with the phase-change temperature of 35-55 DEG C and a photo-thermal reagent. The low-temperature photo-thermal transdermal drug delivery material is smeared on the skin, and then the smeared part is subjected to light treatment, so that the drug transdermal delivery efficiency is improved. According to the invention, the photothermal effect and the phase-change cream are combined to realize accurate control on the photothermal temperature rise of the skin, so that the transdermal transmission efficiency of nano-drugs, water-soluble drugs and proteins is remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of transdermal drug delivery, and specifically relates to a low-temperature photothermal phase change material for assisting transdermal drug delivery, a low-temperature photothermal transdermal drug delivery material and a preparation method. Background Art

[0002] Transdermal drug delivery technology is an important drug delivery method with advantages such as non-invasiveness, convenience and high patient compliance. However, existing transdermal drug delivery systems still face many challenges in improving the transdermal delivery efficiency of drugs. Existing transdermal drug delivery methods have limited delivery efficiency for water-soluble macromolecular drugs and certain bioactive proteins. More efficient transdermal drug delivery strategies continue to be developed.

[0003] Existing technologies mainly promote drug absorption by increasing skin permeability. Common methods include the use of chemical penetration enhancers, ultrasound, microneedle technology, and electroporation. However, these methods are often accompanied by skin damage, irritation, or discomfort, and even have a negative impact on the activity of certain drugs. Therefore, there is an urgent need to develop new transdermal delivery methods. Summary of the invention

[0004] The purpose of the present invention is to provide a low-temperature photothermal phase change material for assisting transdermal drug delivery, a low-temperature photothermal transdermal drug delivery material and a preparation method, which can control the skin temperature through a phase change cream, thereby improving the transdermal delivery efficiency of the drug.

[0005] To achieve the above objectives, the first aspect of the present invention provides a low-temperature photothermal phase change material for assisting transdermal drug delivery, comprising a low-temperature phase change material and a photothermal agent; the photothermal agent is used to convert light energy into thermal energy, and the low-temperature phase change material is used to phase change and absorb heat under the action of the thermal energy to regulate the temperature of the low-temperature photothermal phase change material.

[0006] Further, the phase change temperature of the low temperature phase change material is 35-75°C, preferably 35-55°C, and more preferably 38-43°C;

[0007] And / or, the low temperature phase change material includes one or more of stearic acid, lauric acid, capric acid, myristic acid, and palmitic acid;

[0008] And / or, the photothermal agent is selected from one or more of polydopamine, indocyanine green, graphene, and graphene oxide.

[0009] Furthermore, the low-temperature phase change material includes stearic acid and lauric acid in a mass ratio of 1:(0.5-10), and the mass ratio of stearic acid to lauric acid is preferably 1:(2-8). By regulating the ratio of the two, the phase change temperature is more suitable for the release of the drug into the skin.

[0010] Furthermore, the low-temperature photothermal phase change material also includes a moisturizer, and the moisturizer is preferably glycerin; the viscosity and humidity of the phase change cream are regulated by glycerin, so that the drug has better skin adhesion, thereby improving the release effect.

[0011] Preferably, the mass ratio of the phase change material, the photothermal agent and glycerol is (100-500):(5-50):(20-100), preferably (200-400):(10-30):(40-60).

[0012] The second aspect of the present invention provides a low-temperature photothermal transdermal drug delivery material, comprising any of the above-mentioned low-temperature photothermal phase change materials and a drug to be delivered, preferably a paste.

[0013] Furthermore, the drugs to be delivered include protein macromolecule drugs, small molecule drugs and nanoparticle drugs; the protein macromolecule drugs include insulin, the small molecule drugs include methotrexate, and the nanoparticle drugs include polydopamine nanoparticles.

[0014] Furthermore, the mass ratio of the low-temperature photothermal phase change material and the drug to be delivered is (100-500):(0.01-50), for example, (100-400):(1-40), for example, 100:0.5, 100:2, 100:20, 100:40, 100:50, 500:20, 500:40, etc.

[0015] The third aspect of the present invention provides a method for preparing a low-temperature photothermal transdermal drug delivery material, comprising: melting a phase change material, mixing and grinding it with a photothermal agent and a moisturizer, cooling it to obtain a low-temperature photothermal phase change material, and then mixing it with a drug to be delivered to obtain a low-temperature photothermal transdermal drug delivery material.

[0016] A fourth aspect of the present invention provides a method for using a low-temperature photothermal transdermal drug delivery material, wherein the low-temperature photothermal transdermal drug delivery material is subjected to light treatment to improve drug delivery efficiency.

[0017] Furthermore, the light treatment time is 20-40 minutes, and the temperature of the low-temperature photothermal transdermal drug delivery material is maintained at 38-42°C, preferably 40°C under light treatment;

[0018] After the light treatment is completed, the low-temperature photothermal transdermal drug delivery material applied on the skin is removed, preferably using phosphate buffered saline.

[0019] In general, the above technical solution conceived by the present invention has the following technical advantages compared with the prior art:

[0020] 1. The present invention proposes an innovative low-temperature photothermal transdermal drug delivery method, which utilizes photothermal reagents to achieve photothermal conversion and heat generation, and at the same time utilizes the excellent performance of phase change materials in temperature control to absorb excess heat, thereby achieving gentle photothermal stimulation to the skin, providing an innovative solution for transdermal drug delivery.

[0021] 2. The phase change material of the present invention can accurately control the skin temperature under light and maintain it at about 40°C to promote the transdermal delivery of drugs while avoiding damage to the skin or drugs caused by high temperature. This method can effectively improve the transdermal delivery efficiency of nano drugs, protein drugs, hydrophilic macromolecular drugs, and small molecule drugs, and has significant practical value and broad market prospects. Therefore, the present invention is not only innovative in technology, but also shows good practicality in clinical applications, providing new ideas for the development of transdermal drug delivery technology.

[0022] 3. The present invention adjusts the type and amount of phase change material and photothermal agent, and adds an appropriate amount of glycerol to achieve better heat absorption and temperature control effects, which is more conducive to the rapid release of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 A schematic diagram of the transdermal delivery principle of polydopamine nanoparticles provided by the present invention;

[0024] Figure 2 An optical picture of the phase change cream provided in Example 1;

[0025] Figure 3 This is a confocal image of mouse skin tissue after transdermal delivery of polydopamine nanoparticles provided in Example 1;

[0026] Figure 4 A confocal image of mouse skin tissue after in vivo transdermal delivery of Rhodamine B provided in Example 1;

[0027] Figure 5 This is a graph of blood glucose levels in diabetic mice after transdermal delivery of insulin provided in Example 2; wherein A is a blank control group, B is a subcutaneous injection group, C is without photothermal treatment, and D is with photothermal treatment;

[0028] Figure 6 This is a picture of the skin appearance of psoriasis mice after transdermal delivery of methotrexate provided in Example 3. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0030] The low-temperature photothermal transdermal drug delivery material provided by the present invention comprises a low-temperature photothermal phase change material (phase change cream) and a drug to be delivered. The skin temperature is precisely controlled by the phase change cream, thereby improving the transdermal delivery efficiency of the drug.

[0031] Low-temperature photothermal phase change materials include phase change materials with a phase change temperature of 35-55°C and photothermal agents. Specifically, the following raw materials are included: a phase change material in which stearic acid (SA) and lauric acid (LA) are mixed in a mass ratio of 1:0.5 to 1:10, other phase change materials, polydopamine nanoparticles (PDANPs) and glycerol. Among them, the other phase change materials can be selected from capric acid, myristic acid, palmitic acid and composite phase change materials. The photothermal agent can be one or more selected from polydopamine (PDA), indocyanine green (ICG), graphene oxide, etc.

[0032] The invention provides a method for preparing a phase change material. Stearic acid (SA) and lauric acid (LA) are mixed in proportion, heated and melted, the temperature is maintained at 39-70°C, until they are completely melted, and then naturally cooled to room temperature to obtain the phase change material.

[0033] In some specific embodiments, the method for preparing the phase change cream provided by the present invention comprises the following steps:

[0034] a) placing the prepared phase change material in a water bath and heating it;

[0035] b) adding glycerol and polydopamine nanoparticles into the melted phase change material and mixing them uniformly;

[0036] c) Remove the mixture from the water bath and continue stirring until it forms a cream.

[0037] As a preferred embodiment of the present invention, in step a), the mass of the phase change material is 100-500 mg, in step b), the mass of the glycerol is 20-100 mg, and the mass of the polydopamine nanoparticles is 5-50 mg.

[0038] After the phase change cream prepared in the embodiment of the present invention is applied to the mouse skin and photothermal stimulation is performed using simulated sunlight, the delivery efficiency of the loaded component (drug to be delivered) in the phase change cream in the skin can be effectively promoted.

[0039] The phase change cream prepared in the embodiment of the present invention was applied to the skin of diabetic mice, and after photothermal stimulation, the transdermal delivery of insulin was enhanced and the blood sugar level of the mice was reduced.

[0040] The phase change cream prepared in the embodiment of the present invention was applied to the skin of psoriasis mice. After photothermal stimulation, the transdermal delivery of methotrexate was enhanced and the inflammation of the mice was relieved.

[0041] The transdermal delivered drugs include protein drugs such as insulin, small molecule drugs such as methotrexate, and nano drugs such as polydopamine.

[0042] Under photothermal stimulation, the temperature of the phase-change cream is controlled at about 40° C., and photothermal stimulation is used to enhance the efficiency of drug transdermal delivery.

[0043] The specific implementation of the present invention is described in detail below in conjunction with specific embodiments.

[0044] Example 1

[0045] Low-temperature photothermal transdermal delivery of polydopamine nanoparticles and small molecules, the specific steps are as follows:

[0046] Stearic acid (SA) and lauric acid (LA) are mixed and melted in a mass ratio of 1:5, and the temperature is maintained at 39-70°C until they are completely melted and then naturally cooled to room temperature to obtain a composite phase change material. 300 mg of the SA / LA composite phase change material prepared in Example 1 is weighed and melted in a water bath, and then 20 mg of polydopamine nanoparticles and 50 mg of glycerol are added in sequence and mixed and ground, and then removed from the water bath and gradually cooled to form a cream.

[0047] PDANPs of different sizes (such as 2nm, 200nm and 400nm) were selected as nanomedicines, rhodamine B was used as a small molecule drug model, and the above-mentioned phase change cream was used as a delivery carrier. Photothermal stimulation was performed using simulated sunlight to evaluate its effect on transdermal drug delivery efficiency, as follows:

[0048] BALB / c mice were randomly divided into groups and depilated. After 24 hours, the same transdermal administration process was performed on polydopamine nanoparticles and rhodamine B molecules. First, polydopamine nanoparticles of different sizes (20 mg) or rhodamine B molecules (0.5-2 mg) labeled with fluorescein were incorporated into the phase change cream (100 mg) prepared in Example 1. Then, the phase change cream was applied to the back skin of the mice and irradiated under simulated sunlight for 30 minutes to produce the expected photothermal effect. After photothermal treatment, excess cream was removed with gauze soaked in phosphate buffered saline. After 24 hours, skin sections were prepared and observed by laser confocal microscopy. The results are as shown in FIG. Figure 3 and Figure 4As shown, polydopamine or rhodamine B mainly accumulates in the stratum corneum or epidermis of the skin without photothermal treatment, while photothermal treatment can enhance its transdermal delivery efficiency and reach the dermis.

[0049] Example 2

[0050] Experiments using low-temperature photothermal transdermal strategy to enhance transdermal delivery of insulin for the treatment of diabetes are as follows:

[0051] The phase change cream was prepared by the method of Example 1 and used as a carrier to deliver insulin. Before the insulin transdermal administration experiment, all diabetic mice fasted for 4 hours. Then, insulin was topically applied to the skin in different treatment modes (with or without photothermal treatment, subcutaneous injection and blank control group) for 5 consecutive days, with each dose of 5-10U. Blood glucose changes were monitored every day to evaluate its long-term efficacy. The results are shown in Table 1. Figure 5 As shown. It can be seen that compared with the control group, the blood sugar of mice that were topically applied with insulin cream and then treated with photothermal therapy can be reduced from 30.9mM to 6.2mM within 6 hours, while the blood sugar of mice that were not treated with photothermal therapy did not change significantly, indicating that the low-temperature photothermal transdermal strategy can effectively improve the transdermal delivery efficiency of protein drugs such as insulin while maintaining its function.

[0052] Example 3

[0053] Experiments on enhancing the transdermal delivery of methotrexate for the treatment of psoriasis using low-temperature photothermal transdermal strategy are as follows:

[0054] The phase-changing cream was prepared by the method of Example 1 and used as a carrier to deliver methotrexate. Imiquimod cream (15 mg) was applied to the back skin of mice daily for 7 consecutive days to establish a mouse psoriasis model. Subsequently, on the 6th and 7th days, methotrexate (0.2 mg-0.4 mg) was first incorporated into the polydopamine phase-changing cream (100 mg) prepared in Example 1 and then applied to the back of psoriasis mice for transdermal administration. The appearance of the skin after treatment was as follows: Figure 6 As shown. It can be seen that the skin of mice in the model group was thickened, erythema and scaling appeared, indicating that imiquimod successfully induced a psoriasis mouse model; without photothermal treatment, topical application of polydopamine cream containing methotrexate (MTX) did not significantly relieve the symptoms of psoriasis, while photothermal treatment could significantly relieve the symptoms of psoriasis, indicating that the low-temperature photothermal transdermal strategy can enhance the transdermal delivery effect of methotrexate.

[0055] It can be seen from the above embodiments that the phase change cream of the present invention, through a specific composition, can effectively promote the transdermal drug delivery of polydopamine nanoparticles, insulin, methotrexate and other drugs under light treatment, indicating that this formula has significant advantages in temperature regulation and balance, so that the skin will not be damaged while maintaining permeability, thereby promoting drug penetration.

[0056] It should be noted that the composition of the phase change cream of the present invention can be adjusted according to actual needs, and the type and amount of phase change material and photothermal agent can be adjusted to meet the efficient delivery of different drugs, but it is not limited to this.

[0057] In summary, the present invention proposes a method for promoting transdermal drug delivery by using a cream with precise temperature control function to assist mild photothermal effect. The method combines the photothermal effect with the phase change cream to achieve precise control of the photothermal heating of the skin, thereby significantly improving the transdermal delivery efficiency of nano drugs, water-soluble drugs and proteins. The developed phase change cream contains phase change materials, photothermal materials such as polydopamine nanoparticles and glycerol, which can effectively carry a variety of drugs. Under light irradiation, the temperature of the skin to which the cream is applied rises to the melting point of the phase change material, and the excess heat is absorbed through the phase change process, thereby achieving precise temperature control of ~40°C. The photothermal effect of this temperature control significantly enhances the transdermal delivery of small molecules, macromolecules, protein drugs and nano drugs. The present invention proves that this method improves the transdermal delivery effect of drugs such as insulin and methotrexate.

[0058] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A low-temperature photothermal phase change material for assisting transdermal drug delivery, characterized in that: It includes a low-temperature phase change material with a phase change temperature of 35-75°C and a photothermal agent; the photothermal agent is used to convert light energy into thermal energy, and the low-temperature phase change material is used to phase change and absorb heat under the action of the thermal energy to regulate the temperature of the low-temperature photothermal phase change material.

2. The low-temperature photothermal phase change material according to claim 1, characterized in that: The phase change temperature of the low temperature phase change material is 35-55°C, preferably 38-43°C; The temperature of the low-temperature photothermal phase change material is maintained at 38-43°C by regulation.

3. The low-temperature photothermal phase change material according to claim 1, characterized in that: The low-temperature phase change material includes one or more of stearic acid, lauric acid, decanoic acid, myristic acid, and palmitic acid; And / or, the photothermal agent is selected from one or more of polydopamine, indocyanine green, graphene, and graphene oxide.

4. The low-temperature photothermal phase change material according to claim 3, characterized in that: The low-temperature phase change material comprises stearic acid and lauric acid in a mass ratio of 1:(0.5-10), and the mass ratio of stearic acid to lauric acid is preferably 1:(2-8).

5. The low-temperature photothermal phase change material according to any one of claims 1 to 4, characterized in that: The low-temperature photothermal phase change material further includes a moisturizer, and the moisturizer is preferably glycerin; Preferably, the mass ratio of the low-temperature phase change material, the photothermal agent and glycerol is (100-500): (5-50): (20-100).

6. A low-temperature photothermal transdermal drug delivery material, characterized in that: It comprises the low-temperature photothermal phase change material according to any one of claims 1 to 5 and a drug to be delivered.

7. The low-temperature photothermal transdermal drug delivery material according to claim 6, characterized in that: The drugs to be delivered include protein macromolecule drugs, small molecule drugs and nanoparticle drugs; the protein macromolecule drugs include insulin, the small molecule drugs include methotrexate, and the nanoparticle drugs include polydopamine nanoparticles.

8. The low-temperature photothermal transdermal drug delivery material according to claim 6, characterized in that: The mass ratio of the low-temperature photothermal phase change material to the drug to be delivered is (100-500): (0.01-50).

9. A method for preparing the low-temperature photothermal transdermal drug delivery material according to any one of claims 6 to 8, characterized in that: include: After the phase change material is melted, it is mixed and ground with a photothermal agent and a moisturizer, and cooled to obtain a low-temperature photothermal phase change material, which is then mixed with the drug to be delivered to obtain a low-temperature photothermal transdermal drug delivery material.

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