Ultrasonic responsive lipid drug carrier capable of realizing transdermal drug delivery and preparation method of ultrasonic responsive lipid drug carrier

Abstract

The invention provides an ultrasonic-responsive lipid drug carrier capable of transdermal drug delivery and a preparation method thereof, and the method comprises the following steps: dissolving lipid and a surfactant in an organic solvent, then carrying out rotary evaporation to remove the organic solvent and form a lipid film, then adding an aqueous solution to hydrate the film, and finally adding an ultrasonic-responsive substance to obtain the ultrasonic-responsive lipid drug carrier capable of transdermal drug delivery. The ultrasonic responsive lipid drug carrier capable of realizing transdermal drug delivery is obtained. The lipid drug carrier disclosed by the invention is nanoscale, has good deformability and ultrasonic responsiveness, and is suitable for skin delivery and deep administration of water-soluble or fat-soluble drugs. The lipid drug carrier is combined with ultrasound, so that a drug delivery system capable of noninvasively realizing deep transdermal drug delivery can be formed, and the problems of low drug delivery efficiency, poor safety, insufficient drug penetration depth and the like in the prior art can be effectively solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an ultrasound-responsive lipid drug carrier capable of transdermal administration and a preparation method thereof. Background Art

[0002] Transdermal administration is the third largest route of administration after oral and injection administration. It has the advantages of reducing the fluctuation of drug concentration in the blood, reducing toxic and side effects, convenient administration, and good patient compliance. Its synergistic strategies are divided into passive administration and active administration. Passive administration is mainly divided into two categories. Chemical permeants are used to destroy the skin barrier to promote penetration. They are highly toxic and may cause skin irritation, which has certain risks. Drug carriers can encapsulate water-soluble or fat-soluble drugs, such as liposomes, nanoparticles, nanoemulsions, etc., but the administration efficiency is low when used alone. Active administration refers to the use of physical methods to promote drug penetration, such as ion introduction, laser, microneedle, ultrasound and other methods. These methods aim to use external energy to effectively destroy the stratum corneum barrier and improve the efficiency of drug penetration through the stratum corneum. Compared with a single administration method, the combination of passive and active methods can achieve more efficient administration. However, the current efficiency of combined administration methods has not yet met the needs of clinical applications. In addition, the existing methods are mainly aimed at the stratum corneum. Once the drug penetrates the stratum corneum barrier, how to control its subsequent transportation and deep dermal delivery has not yet been solved. In the existing methods, the drug penetration depth is insufficient when combined with ion introduction or laser delivery, mostly below 500μm; when the microneedle delivery depth exceeds 960μm, there is obvious pain, and when it exceeds 1450μm, there is a risk of bleeding and infection. It cannot meet the needs of some diseases that require deep drug delivery.

[0003] Therefore, it is necessary to seek more efficient, safe and controllable transdermal drug delivery methods to achieve efficient, sufficient and deep drug delivery, and provide a new strategy for transdermal drug delivery treatment of more clinical diseases. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide an ultrasound-responsive lipid drug carrier for transdermal administration and a preparation method thereof in view of the deficiencies of the above-mentioned prior art. The lipid drug carrier can stably encapsulate ultrasound-responsive substances, has good deformability and ultrasonic responsiveness, and can achieve the goal of efficient, sufficient and deep transdermal 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 an ultrasound-responsive lipid drug carrier that can be administered transdermally, the method comprising the following steps:

[0007] S1, dissolving lipid and surfactant in an organic solvent, and mixing to obtain a mixed solution;

[0008] S2, taking the mixed solution obtained in S1 and placing it in a rotary evaporator, removing the organic solvent under vacuum conditions and forming a lipid film;

[0009] S3, adding a hydration solution to the lipid film obtained in S2, and letting it stand for 8 to 16 hours to hydrate the film to obtain a hydrated film;

[0010] S4. Place the hydrated film obtained in S3 in an ice bath, and ultrasonicate for 2 to 10 minutes at a power of 30 to 150 W to form a lipid drug carrier, then add an ultrasonic responsive substance, and continue ultrasonicating for 2 to 10 minutes. The resulting solution is filtered through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

[0011] Preferably, the lipid in S1 is one or more of phosphatidylcholine, phosphatidylethanolamine or phosphatidylglycerol;

[0012] Preferably, the surfactant in S1 is one of Span 80, Span 20, Tween 80, Tween 20, sodium cholate or sodium deoxycholate; the surfactant can enhance the flexibility of the lipid membrane, so that it has good deformability to pass through the stratum corneum barrier.

[0013] Preferably, the mass ratio of the lipid to the surfactant in S1 is 70:30 to 95:5.

[0014] Preferably, the organic solvent in S1 is one or more of chloroform, methanol, ethanol or dichloromethane.

[0015] Preferably, the temperature of the rotary evaporator in S2 is 30-70° C. and the rotation speed is 60-90 rpm.

[0016] Preferably, the hydration solution in S3 is deionized water or phosphate buffer.

[0017] Preferably, the ultrasound responsive substance in S4 is perfluorocarbon, specifically one or more of perfluoropentane or perfluorohexane, and the added amount is based on a volume ratio of perfluorocarbon to hydration solution of 1:(5-100).

[0018] Preferably, when the administrable drug is a water-soluble drug, the water-soluble drug is dissolved in the hydration solution of step S3.

[0019] Preferably, when the administrable drug is a fat-soluble drug, the fat-soluble drug is dissolved in the organic solvent of step S1.

[0020] The present invention also provides an ultrasound-responsive lipid drug carrier that can be administered transdermally and is prepared by the above method.

[0021] The present invention also provides an application of the ultrasound-responsive lipid drug carrier capable of transdermal administration, which can be used for skin delivery and deep administration of water-soluble or fat-soluble drugs.

[0022] The present invention has significant technical effects due to the adoption of the above technical solution:

[0023] 1. The present invention provides a nano-scale lipid drug carrier suitable for transdermal administration, which can stably encapsulate ultrasound-responsive substances and has good deformability and ultrasonic responsiveness. The lipid drug carrier combined with ultrasound can achieve deep skin delivery of drugs in a non-invasive and safe manner, effectively solving the problems of low drug administration efficiency, poor safety, and insufficient drug penetration depth in the prior art.

[0024] 2. The present invention combines lipid drug carriers with ultrasound, showing good ultrasonic responsiveness, and forming a drug delivery system that can achieve deep transdermal administration non-invasively. First, the deformability of lipid drug carriers is utilized, and the intact structure can be maintained and the epidermis can be efficiently penetrated under the drive of the hydration gradient without destroying the stratum corneum structure. Ultrasound is then applied to trigger the ultrasonic response substance in the drug carrier to undergo a liquid-gas phase change, that is, from a liquid state to a gaseous state, resulting in expansion and eventual rupture. The micro-jets and mechanical friction effects generated after ultrasound acts on the drug carrier are supplemented from the inside to promote the drug to diffuse further into the deep dermis, thereby achieving the purpose of delivering a large amount of drugs to the deep layer. The process can adjust the response intensity by controlling the amount of ultrasonic response substance (PFP) and ultrasonic parameters to ensure safety.

[0025] The present invention is further described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is a transmission electron micrograph of the ultrasound-responsive lipid drug carrier that can be used for transdermal administration in Example 4 of the present invention;

[0027] Figure 2 This is a particle size distribution diagram of the ultrasound-responsive lipid drug carrier that can be used for transdermal administration in Example 4 of the present invention;

[0028] Figure 3 This is a graph showing changes in particle size and zeta potential of an ultrasound-responsive lipid drug carrier that can be used for transdermal administration in Example 4 of the present invention within seven days;

[0029] Figure 4 These are optical images of the ultrasound-responsive lipid drug carrier that can be used for transdermal administration at different ultrasound irradiation times in Example 4 of the present invention. DETAILED DESCRIPTION

[0030] Example 1

[0031] This embodiment is a method for preparing an ultrasound-responsive lipid drug carrier that can be administered transdermally, wherein the drug is a fat-soluble drug triamcinolone acetonide, and the method comprises the following steps:

[0032] S1. Dissolve 34 mg of phosphatidylcholine and 6 mg of Tween 20 in 18 mL of dichloromethane, and then add 25 mg of triamcinolone acetonide and mix well to obtain a mixed solution;

[0033] S2, adding the mixed solution obtained in S1 into a round-bottom flask, and then placing the round-bottom flask in a rotary evaporator, and operating under vacuum conditions of a temperature of 55° C. and a rotation speed of 90 rpm until the organic solvent is evaporated and removed, and a lipid film is formed at the bottom of the round-bottom flask;

[0034] S3, adding 10 mL of phosphate buffer solution (PBS solution, pH 7.4) to the lipid film obtained in S2, and letting it stand for 12 h to hydrate the film to obtain a hydrated film;

[0035] S4. Place the hydrated film obtained in S3 in an ice bath and sonicate for 5 min at a power of 120 W to form a lipid drug carrier. Then add 200 μL of perfluoropentane and 200 μL of perfluorohexane (1:1, v / v), and continue sonicating for 5 min. The resulting solution is filtered through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

[0036] The particle size of the ultrasound-responsive lipid drug carrier for transdermal administration obtained in this example is 200 nm.

[0037] Example 2

[0038] This embodiment is a method for preparing an ultrasound-responsive lipid drug carrier that can be administered transdermally, wherein the drug is a fat-soluble drug triamcinolone acetonide, and the method comprises the following steps:

[0039] S1. Dissolve 12 mg of phosphatidylcholine and 3 mg of Tween 80 in a mixed solvent of 8 mL of chloroform and 4 mL of methanol, and then add 20 mg of triamcinolone acetonide and mix well to obtain a mixed solution;

[0040] S2, adding the mixed solution obtained in S1 into a round-bottom flask, and then placing the round-bottom flask in a rotary evaporator, and operating under vacuum conditions of a temperature of 70° C. and a rotation speed of 65 rpm until the organic solvent is evaporated and removed, and a lipid film is formed at the bottom of the round-bottom flask;

[0041] S3, adding 8 mL of PBS solution (pH 7.4) to the lipid film obtained in S2, and letting it stand for 8 h to hydrate the film to obtain a hydrated film;

[0042] S4. Place the hydrated film obtained in S3 in an ice bath, and sonicate for 4 minutes at a power of 90 W to form a lipid drug carrier. Then add 300 μL of perfluoropentane and continue sonicating for 4 minutes. The resulting solution is filtered through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

[0043] The particle size of the ultrasound-responsive lipid drug carrier for transdermal administration obtained in this example is 210 nm.

[0044] Example 3

[0045] This embodiment is a method for preparing an ultrasound-responsive lipid drug carrier that can be administered transdermally. The drug is a water-soluble drug 5-fluorouracil (5-FU). The method comprises the following steps:

[0046] S1. Dissolve 15 mg of phosphatidylethanolamine, 3 mg of cholesterol and 3 mg of sodium cholate in 8 mL of chloroform and mix well to obtain a mixed solution;

[0047] S2, adding the mixed solution obtained in S1 into a round-bottom flask, and then placing the round-bottom flask in a rotary evaporator, and operating under vacuum conditions of a temperature of 60° C. and a rotation speed of 60 rpm until the organic solvent is evaporated and removed, and a lipid film is formed at the bottom of the round-bottom flask;

[0048] S3, adding 10 mL of PBS solution containing 2% 5-FU (w / v) to the lipid film obtained in S2, and letting it stand for 16 h to hydrate the film to obtain a hydrated film;

[0049] S4. Place the hydrated film obtained in S3 in an ice bath, and sonicate for 6 minutes at a power of 150 W to form a lipid drug carrier. Then add 200 μL of perfluorohexane and continue sonicating for 6 minutes. The resulting solution is filtered through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

[0050] The particle size of the ultrasound-responsive lipid drug carrier for transdermal administration obtained in this example is 180 nm.

[0051] Example 4

[0052] This embodiment is a method for preparing an ultrasound-responsive lipid drug carrier that can be administered transdermally. The drug is a water-soluble drug 5-fluorouracil (5-FU). The method comprises the following steps:

[0053] S1. Dissolve 20 mg of phosphatidylcholine and 5 mg of Span 80 in a mixed solvent of 12 mL of chloroform and 4 mL of methanol, and mix well to obtain a mixed solution;

[0054] S2, adding the mixed solution obtained in S1 into a round-bottom flask, and then placing the round-bottom flask in a rotary evaporator, and operating under vacuum conditions of a temperature of 60° C. and a rotation speed of 80 rpm until the organic solvent is evaporated and removed, and a lipid film is formed at the bottom of the round-bottom flask;

[0055] S3, adding 15 mL of deionized water containing 1% 5-FU (w / v) to the lipid film obtained in S2, and letting it stand for 12 h to hydrate the film to obtain a hydrated film;

[0056] S4. Place the hydrated film obtained in S3 in an ice bath, and sonicate for 6 min at a power of 60 W to form a lipid drug carrier, then add 150 μL of perfluoropentane and continue sonicating for 4 min. Filter the resulting solution through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

[0057] The morphology of the ultrasound-responsive lipid drug carrier for transdermal administration prepared by the present invention was observed by transmission electron microscopy (TEM), and it was found that the carrier was spherical with a particle size of about 200 nm (see Figure 1 ). A laser particle size analyzer was used to measure the particle size distribution of lipid drug carriers (see Figure 2 ) and zeta potential (see Figure 3 ),from Figure 2 From the particle size distribution diagram, we can see that the particle size is about 200nm, which is consistent with the TEM results, and this particle size is suitable for transdermal administration. Figure 3 The particle size and zeta potential change graphs over seven days showed no significant changes in particle size or zeta potential of the lipid drug carrier, indicating that it was stable within a week.

[0058] In order to observe the changes of lipid drug carriers under ultrasound, an optical microscope was used to observe the changes of lipid drug carriers in real time within 60 minutes of ultrasound. Figure 4 It can be seen that within 40 minutes of ultrasonic irradiation, the ultrasonic responsive substance in the carrier undergoes a phase change, generates microbubbles and gradually bursts. As the ultrasonic action time increases, the ultrasonic responsive substance gradually disappears, so the phase change process after 40 minutes is significantly weakened.

[0059] 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 an ultrasound-responsive lipid drug carrier for transdermal administration, characterized in that: The method comprises the following steps: S1, dissolving lipid and surfactant in an organic solvent, and mixing to obtain a mixed solution; S2, taking the mixed solution obtained in S1 and placing it in a rotary evaporator, removing the organic solvent under vacuum conditions and forming a lipid film; S3, adding a hydration solution to the lipid film obtained in S2, and letting it stand for 8 to 16 hours to hydrate the film to obtain a hydrated film; S4. Place the hydrated film obtained in S3 in an ice bath, and ultrasonicate for 2 to 10 minutes at a power of 30 to 150 W to form a lipid drug carrier, then add an ultrasonic responsive substance, and continue ultrasonicating for 2 to 10 minutes. The resulting solution is filtered through a polycarbonate membrane to obtain an ultrasound-responsive lipid drug carrier that can be administered transdermally, and store it at a temperature below 4°C.

2. The method according to claim 1, characterized in that The lipid in S1 is one or more of phosphatidylcholine, phosphatidylethanolamine or phosphatidylglycerol; the surfactant is one of Span 80, Span 20, Tween 80, Tween 20, sodium cholate or sodium deoxycholate; the mass ratio of the lipid to the surfactant is 70:30 to 95:

5.

3. The method according to claim 1, characterized in that The organic solvent in S1 is one or more of chloroform, methanol, ethanol or dichloromethane.

4. The method according to claim 1, characterized in that The temperature of the rotary evaporator in S2 is 30-70°C and the rotation speed is 60-90 rpm.

5. The method according to claim 1, characterized in that The hydration solution in S3 is deionized water or phosphate buffer.

6. The method according to claim 1, characterized in that The ultrasonic response substance in S4 is perfluorocarbon, specifically one or more of perfluoropentane or perfluorohexane, and the added amount is based on the volume ratio of perfluorocarbon to hydration solution of 1: (5-100).

7. The method according to claim 1, characterized in that When the administered drug is a water-soluble drug, the water-soluble drug is dissolved in the hydration solution of step S3.

8. The method according to claim 1, characterized in that When the drug to be administered is a fat-soluble drug, the fat-soluble drug is dissolved in the organic solvent of step S1.

9. An ultrasound-responsive lipid drug carrier for transdermal administration prepared by the method according to any one of claims 1 to 8.

10. A use of the ultrasound-responsive lipid drug carrier for transdermal administration according to claim 9, characterized in that: The transdermally administrable ultrasound-responsive lipid drug carrier can be used for skin delivery and deep-layer administration of water-soluble or fat-soluble drugs.

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