WO2023024338A1 - Piezoelectret drug delivery patch in combination with transdermal drug delivery by means of pressing or patting, and preparation method therefor and application thereof - Google Patents

Piezoelectret drug delivery patch in combination with transdermal drug delivery by means of pressing or patting, and preparation method therefor and application thereof Download PDF

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Publication number
WO2023024338A1
WO2023024338A1 PCT/CN2021/137768 CN2021137768W WO2023024338A1 WO 2023024338 A1 WO2023024338 A1 WO 2023024338A1 CN 2021137768 W CN2021137768 W CN 2021137768W WO 2023024338 A1 WO2023024338 A1 WO 2023024338A1
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layer
piezoelectric electret
drug delivery
drug
electret
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PCT/CN2021/137768
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French (fr)
Chinese (zh)
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方鹏
曹江浪
李光林
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中国科学院深圳先进技术研究院
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Publication of WO2023024338A1 publication Critical patent/WO2023024338A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents

Definitions

  • the invention belongs to the technical field of transdermal drug delivery preparations, in particular to a piezoelectric electret drug delivery patch and its preparation method and application, in particular to a piezoelectric electret combined with contact pressure or tapping for transdermal drug delivery Drug delivery patch and its preparation method and application.
  • Drugs applied on the surface of the skin enter the systemic circulation by penetrating the skin by themselves, or use a certain method to make the drug enter the systemic circulation through the skin at a constant or near constant rate, thereby producing systemic or local therapeutic effects.
  • This method of administration is called Transdermal administration.
  • Drugs applied on the surface of the skin are conducted to the inside of the skin through natural penetration, but due to the barrier effect of the stratum corneum of the skin, the conduction efficiency of the active ingredients is low, and most of the active ingredients remain on the surface of the skin, making it difficult to penetrate into the subcutaneous area.
  • some devices are too bulky and inconvenient to use, some have too complicated a process, and some have insignificant electrostatic field effects.
  • CN105457151A discloses a process for transdermal administration of ultrasonic and electrostatic combined burn ointment.
  • a reservoir-type patch body is used, including a backing layer, a burn ointment layer and a tourmaline powder layer arranged sequentially from the outside to the inside, and also includes an electret layer made of electret material and a Controlled-release film layer; the electret layer is located outside the backing layer, and the controlled-release film layer is located between the burn ointment layer and the tourmaline powder layer;
  • the main body of the storage-type patch also includes an ultrasonic wave generation layer, and the ultrasonic wave The occurrence layer is located on both sides of the burn cream layer and clamps the burn cream layer.
  • CN106074460A discloses a transdermal preparation for inhibiting hypertrophic scar growth in combination with electret and 5-fluorouracil.
  • the transdermal drug delivery preparation proposed by this invention includes a backing layer, the inner side of the backing layer is provided with a drug-containing pressure-sensitive adhesive layer, and the outer side of the backing layer is provided with an electret layer made of electret material, The electret layer, the backing layer, and the drug-containing pressure-sensitive adhesive layer form a storage-type patch.
  • the electret layer is provided with an electric energy input end, and the electric energy input end is connected with a microprocessor system, and the microprocessor system is connected with a time module.
  • the invention can change the viscosity of the patch and the polarization parameters of the drug through the electret to regulate the release of the drug.
  • the feedback system based on the microprocessor system described in this invention will make the size of the transdermal drug delivery preparation too large, and the convenience of use will be affected.
  • CN109718465A discloses a 3D printing electret microneedle to promote absorption mask, including a 3D printed mask layer, the mask layer contains a matrix of skin care active ingredients, the lower surface of the mask layer is covered with a microneedle array layer; the microneedle array layer includes The base layer used to fix the microneedles, the base layer is fixed with hollow microneedles at equal intervals, the hollow part of the microneedles forms a drug delivery channel, the upper end of the drug delivery channel penetrates into the mask layer, and the lower end faces outward; the upper surface of the mask layer The top is covered with an isolation layer, and the upper surface of the isolation layer is covered with an electret layer.
  • an electret layer and a microneedle layer are added on the mask layer, and the micro-current and electrostatic field generated by the electret can be used to promote the penetration of the matrix into the inner layer of the skin.
  • a microprocessor system is used to connect the metal electrode layer outside the electret layer to realize the control of the electrostatic field and microcurrent in the electret. Because the control voltage output by the microprocessor system cannot reach the polarization voltage of the electret, it is difficult to effectively regulate the electrostatic field and micro-current in the electret.
  • Piezoelectret is a new type of transducing material with high sensitivity coefficient and good flexibility. It has good flexibility and piezoelectric effect, and is not affected by pyroelectric effect. It can convert weak force change signals into current pulses . Piezoelectric electrets can be prepared through processes such as pore structure treatment and polarization, and are often used in high-sensitivity force sensors, vibration sensors, energy harvesters, etc.
  • piezoelectric electrets can be used in the field to prepare a drug patch with small volume, convenient use and simple process, so as to improve the drug absorption rate of transdermal administration.
  • the purpose of the present invention is to provide a piezoelectric electret drug delivery patch combined with touch pressure or tap transdermal drug delivery, its preparation method and application.
  • the piezoelectric electret drug delivery patch promotes transdermal drug delivery by touching or tapping, has a simple use method and is easy to prepare, and has good application prospects.
  • the present invention provides a piezoelectret drug delivery patch combined with touch pressure or tap transdermal administration, which includes a covering layer, a piezoelectret layer and a drug layer that are sequentially stacked;
  • the electroelectret layer includes a piezoelectric electret and a metal electrode combined with the piezoelectric electret.
  • the piezoelectric electret is a key component in the transdermal drug delivery patch.
  • Piezoelectric electret is a new type of piezoelectric material based on polymer space charge electret, which has good flexibility and piezoelectric effect, and is not affected by pyroelectric effect; metal electrodes are set on the surface of piezoelectric electret , the metal electrode provides compensation charges for the electric dipole in the piezoelectric electret; when the piezoelectric electret is pressed or tapped by an external force in its vertical direction, its internal pore structure is compressed, and the internal electric dipole As the dipole moment of the pole decreases, the compensation charge in the metal electrode also decreases accordingly. Therefore, a changing charge signal will be generated in the metal electrode, thereby generating a microcurrent pulse.
  • the force generated by touching or tapping the piezoelectric electret will cause microcurrent pulses to be generated in the metal electrodes, and the skin will Under the action of microcurrent pulses, the keratin in the stratum corneum forms polypeptide chains arranged in parallel by the polypeptide chains of ⁇ -helical structure, and the mutual repulsion between the adjacent dipoles leads to the generation of new cells in the interstitial cells of the stratum corneum.
  • the defect of the skin changes the arrangement structure of the stratum corneum lamellar lipids, thereby improving the fluidity of skin lipids, expanding the channels for drug molecules to enter and penetrate the stratum corneum of the skin, and facilitating the percutaneous penetration of drugs.
  • the method of touching or tapping the piezoelectric electret is not limited, and the strength and frequency of touching or tapping the piezoelectric electret are determined according to the actual use; the specific duration of touching or tapping the piezoelectric electret depends on the drug.
  • the drug composition of the layer and its method of use are determined.
  • the specific touch pressure and touch time need to be determined according to the sensitivity coefficient d33 of the piezoelectric electret, the smaller the sensitivity coefficient d33 , the greater the required touch force and the longer the touch time.
  • the metal electrode is arranged between the piezoelectric electret and the drug layer.
  • the area of the metal electrode is smaller than or equal to the area of the piezoelectric electret.
  • the covering layer has an area larger than that of the piezoelectric electret layer.
  • the cover layer described in the present invention is beneficial to protect the piezoelectric electret layer, and the area of the cover layer is larger than the piezoelectric electret layer and is in contact with the skin; if the piezoelectric electret is thicker, it is not necessary to place a cover Layer, touch or tap directly on the side of the piezoelectric electret that is not plated with metal electrodes.
  • the thickness of the piezoelectric electret layer includes but is not limited to 10 ⁇ m ⁇ 1000 ⁇ m, such as 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 50 ⁇ m, 80 ⁇ m, 100 ⁇ m, 150 ⁇ m, 200 ⁇ m, 250 ⁇ m, 280 ⁇ m, 300 ⁇ m, 350 ⁇ m, 400 ⁇ m, 450 ⁇ m, 500 ⁇ m, 550 ⁇ m, 600 ⁇ m, 650 ⁇ m, 700 ⁇ m, 750 ⁇ m, 8000 ⁇ m, 8500 ⁇ m , 950 ⁇ m or 1000 ⁇ m, etc.
  • the specific thickness can be determined according to the properties of the electret material used.
  • the area of the piezoelectric electret in the present invention can be determined according to the actual transdermal administration area.
  • the polymer material used in the piezoelectric electret can be a material with good biocompatibility, including but not limited to polypropylene (PP), fluorinated ethylene propylene polymer (FEP), polytetrafluoroethylene Any one of ethylene (PTFE), perfluoroalkoxy resin (PFA), polychlorotrifluoroethylene (PCTFE), polyvinylidene fluoride (PVDF) or polyethylene naphthalate (PEN) or at least A combination of the two.
  • PP polypropylene
  • FEP fluorinated ethylene propylene polymer
  • PFA perfluoroalkoxy resin
  • PCTFE polychlorotrifluoroethylene
  • PVDF polyvinylidene fluoride
  • PEN polyethylene naphthalate
  • the metal forming the metal electrode is gold (Au) and/or silver (Ag).
  • the metal electrode is located on the surface of the piezoelectric electret, and can be plated on the surface of the piezoelectric electret by magnetron sputtering, chemical vapor deposition and other coating processes, and the metal used for the coating is a metal that is harmless to the human body. , including but not limited to metals such as gold or silver; meanwhile, the metal electrode is arranged between the piezoelectric electret and the drug layer.
  • the thickness of the metal electrode includes but is not limited to 10 nm to 1000 nm, for example, 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 50 ⁇ m, 80 ⁇ m, 100 ⁇ m, 150 ⁇ m, 200 ⁇ m, 250 ⁇ m, 280 ⁇ m, 300 ⁇ m, 350 ⁇ m, 400 ⁇ m, 450 ⁇ m, 500 ⁇ m, 550 ⁇ m, 600 ⁇ m, 650 ⁇ m, 700 ⁇ m, 750 ⁇ m, 800 ⁇ m, 850 ⁇ m, 900 ⁇ m, 950 ⁇ m or 1000 ⁇ m, etc.
  • the specific thickness can be determined according to the properties of the electret material used.
  • the thickness of the metal electrode includes but is not limited to tens of nanometers to several thousand nanometers, preferably 10 nm ⁇ 1000 nm, such as 10 nm, 20 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm or 1000 nm etc.
  • the drug layer is formed by a medical dressing that is in contact with the skin and contains drugs or a drug that is directly applied to the skin;
  • the drug layer is formed by applying ointment or medicinal solution on the skin surface, or by soaking the ointment or medicinal solution with a few microns of medical cotton film and other materials and sticking it on the skin surface.
  • Actual transdermal administration includes, but is not limited to, the formation of a drug layer in the above-mentioned manner.
  • the metal electrode side of the piezoelectric electret is placed on the drug layer so that the metal electrode is in contact with the drug layer or the skin.
  • the cover layer placed on the piezoelectric electret is made of harmless film material, its thickness is not limited, and its size is larger than that of the piezoelectric electret.
  • the covering layer is in contact with the piezoelectric electret layer and the skin for covering the piezoelectric electret.
  • the present invention provides a method for preparing the piezoelectric electret drug delivery patch as described in the first aspect, the preparation method comprising:
  • the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
  • the metal electrodes on the piezoelectric electret layer are combined with the piezoelectric electret by a coating method.
  • the coating method includes magnetron sputtering and/or chemical vapor deposition.
  • the preparation method of the piezoelectric electret includes the steps of obtaining a pore structure and polarization.
  • the method for obtaining the pore structure includes, but is not limited to, any one or a combination of at least two of puffing, template or etching.
  • the polarization method includes but not limited to corona polarization method, electron beam polarization method or radiation polarization method.
  • the preparation method comprises the following steps:
  • the polymer material is processed by the puffing method to obtain a pore structure, and then polarized by the electron beam irradiation polarization method to obtain a piezoelectric electret;
  • the thickness of the metal electrode is 10 nm to 1000 nm nm, thereby obtaining a piezoelectret layer comprising a piezoelectret and a metal electrode;
  • a drug layer which is a medical dressing that contacts the skin and contains drugs
  • the covering layer is prepared, and then the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
  • the piezoelectric electret drug delivery patch can be used according to the following method:
  • a drug layer is set on the skin by smearing or sticking;
  • the side of the piezoelectric electret coated with the metal electrode is covered on the drug layer, so that the metal electrode contacts the skin or the drug layer, and a covering layer is placed on the side of the piezoelectric electret that is not plated with the metal electrode;
  • materials such as the covering layer, piezoelectric electret and drug layer applied on the skin can be cleaned off.
  • the present invention provides an application of the piezoelectric electret drug delivery patch as described in the first aspect in the preparation of a transdermal drug delivery system.
  • the piezoelectric electret drug delivery patch of the present invention can be used in scenes with small wounds or weak pain, such as blood stasis and swelling, traditional Chinese medicine massage, beauty and skin care and other fields.
  • the present invention provides a piezoelectric electret drug delivery patch combined with contact pressure or tap transdermal drug delivery.
  • the drug delivery patch includes a covering layer, a piezoelectric electret,
  • the internal hole structure of the piezoelectric electret is compressed, the dipole moment of the internal electric dipole is reduced, and the compensation charges in the metal electrode are also reduced.
  • microcurrent pulses are generated. Under the action of microcurrent pulses, the keratin in the stratum corneum of the skin is arranged in parallel by the polypeptide chains of the ⁇ -helical structure.
  • the method of touching or tapping the piezoelectric electret is not limited, and the strength and frequency of touching or tapping are determined according to the actual use conditions, and the specific use time depends on the drug composition of the drug layer and Its use method is determined; therefore, the use of the piezoelectric electret drug delivery patch is less restricted and has a wider use range, and is suitable for preparing various types of transdermal drug delivery systems.
  • Fig. 1 is a schematic structural diagram of the piezoelectric electret drug delivery patch provided by the present invention, wherein 1 - covering layer, 2 - drug layer, 3 - metal electrode, 4 - piezoelectric electret.
  • Fig. 2 is a flow chart of the use of the piezoelectric electret drug delivery patch provided by the present invention.
  • FIG. 1 The structure of the piezoelectric electret drug delivery patch combined with contact pressure or tapping transdermal drug delivery provided by the present invention is shown in Figure 1, consisting of a covering layer 1, a piezoelectric electret layer and a drug layer 2;
  • the piezoelectric electret layer includes a piezoelectric electret 4 and a metal electrode 3 plated on one side of the piezoelectric electret.
  • the drug layer 2 can be placed on the skin surface simultaneously with the piezoelectric electret layer;
  • the materials such as the covering layer 1, the piezoelectric electret 4, and the drug layer 2 applied on the skin can be cleaned; wherein, the touching or patting
  • the specific method, duration and frequency of the piezoelectric electret can be determined according to the drug composition of the drug layer 2 or the actual use;
  • the force generated by touching or tapping the piezoelectric electret 4 causes microcurrent pulses to be generated in the metal electrodes; Under this condition, the fluidity of skin lipids increases, which expands the channel for drug molecules to enter and penetrate the stratum corneum of the skin, which is conducive to the percutaneous penetration of drugs.
  • the piezoelectric electret 4 used is a polypropylene piezoelectric electret.
  • Polypropylene piezoelectric electret can be prepared by the following method:
  • the polypropylene film is subjected to pore structure treatment, so that the inside of the film has a microporous structure, and the microporous treatment conditions can be used but not limited to the pressure of 2 MPa, the temperature of 110 °C, and the time of 3 h in a nitrogen environment and other conditions;
  • the polarization conditions can be but not limited to needle pressure 20 kV, grid voltage 5 kV, time 2 min and other conditions.
  • This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
  • the piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret
  • the thickness of the piezoelectric electret layer is 200 ⁇ m, wherein the average thickness of the metal electrode 3 is 400 nm, and the area of the metal electrode 3 is smaller than the area of the piezoelectric electret 4;
  • the drug layer 2 is medical gauze soaked in ointment, the covering layer 1 is a medical bandage, and the area of the covering layer 1 is larger than the area of the piezoelectric electret layer;
  • the piezoelectric electret drug delivery patch can be cut according to the actual required area.
  • This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
  • the piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret
  • the thickness of the piezoelectric electret layer is 500 ⁇ m, wherein the average thickness of the metal electrode 3 is 100 nm, and the area of the metal electrode 3 is less than or equal to the area of the piezoelectric electret 4;
  • the drug layer 2 is medical gauze soaked in ointment, the covering layer 1 is a medical bandage, and the area of the covering layer 1 is larger than the area of the piezoelectric electret layer;
  • the piezoelectric electret drug delivery patch can be cut according to the actual required area.
  • This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
  • the piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret
  • the thickness of the piezoelectric electret layer is 20 ⁇ m, wherein the average thickness of the metal electrode 3 is 50 nm, and the area of the metal electrode 3 is smaller than the area of the piezoelectric electret 4;
  • the drug layer 2 is not a medical gauze soaked in ointment, but a drug directly applied on the skin surface; the covering layer 1 is a medical bandage.
  • This embodiment provides a method for using a piezoelectric electret drug delivery patch, the method for using includes the following steps:
  • This embodiment provides a method for using a piezoelectric electret drug delivery patch, the method for using includes the following steps:
  • the force used for tapping or touching in Embodiment 4 and Embodiment 5 is provided by an existing tapping or touching device, and the force provided by tapping or touching is a uniform and controllable force.
  • Example 1 The only difference from Example 1 is that in this comparative example, no piezoelectric electret layer is placed in the piezoelectric electret drug delivery patch, only the covering layer 1 and the drug layer 2 .
  • the piezoelectric electret has high sensitivity to the detection of dynamic force.
  • the piezoelectric electret can output a current of several hundred microamperes at most, which can The skin has a direct electrical stimulation effect.
  • the experimental data show that the polypropylene piezoelectric electret with a piezoelectric coefficient d 33 of 155 pC/N can output a stimulation current of up to 500 ⁇ A under a contact force of 10 N.
  • Piezoelectric electret drug delivery patches are pasted on the skin, and the concentration of drug molecules in the skin is detected after being pressed for a period of time.
  • Example 3 The experimental results also show that the concentration of drug molecules in the skin of Example 3 is at least 1.2 times higher than that of Example 1 and Example 2. This is due to the fact that the piezoelectric electret with a small thickness can release a larger stimulating current when it is pressed. Therefore, the piezoelectric electret drug delivery patch has a more obvious effect on promoting skin absorption of drug molecules.

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Abstract

A piezoelectret (4) drug delivery patch in combination with transdermal drug delivery by means of pressing or patting, and a preparation method therefor and an application thereof. The piezoelectret (4) drug delivery patch comprises a covering layer (1), a piezoelectret layer, and a drug layer (2), which are sequentially arranged in a stacked manner, wherein the piezoelectret layer comprises a piezoelectret (4), and a metal electrode (3), which is combined with the piezoelectret (4). By means of pressing or patting, the piezoelectret (4) drug delivery patch generates a micro-current pulse, such that the fluidity of skin lipoids is improved, and drug molecules enter channels which penetrate the stratum corneum of skin to expand, thereby significantly improving the transdermal permeation efficiency of a drug.

Description

一种结合触压或拍打透皮给药的压电驻极体给药贴剂及其制备方法和应用A piezoelectric electret drug delivery patch combined with touch pressure or tap transdermal drug delivery and its preparation method and application 技术领域technical field
本发明属于透皮给药制剂技术领域，具体涉及一种压电驻极体给药贴剂及其制备方法和应用，尤其涉及一种结合触压或拍打透皮给药的压电驻极体给药贴剂及其制备方法和应用。The invention belongs to the technical field of transdermal drug delivery preparations, in particular to a piezoelectric electret drug delivery patch and its preparation method and application, in particular to a piezoelectric electret combined with contact pressure or tapping for transdermal drug delivery Drug delivery patch and its preparation method and application.
背景技术Background technique
涂抹在皮肤表面的药物以自行渗透皮肤的方式进行体循环，或者采用某种方式使药物以恒定速率或接近恒定速率通过皮肤进入体循环，从而产生全身或局部治疗作用，这种给药方式称之为透皮给药。Drugs applied on the surface of the skin enter the systemic circulation by penetrating the skin by themselves, or use a certain method to make the drug enter the systemic circulation through the skin at a constant or near constant rate, thereby producing systemic or local therapeutic effects. This method of administration is called Transdermal administration.
涂抹在皮肤表面的药物通过自然渗透传导到皮肤内部，但由于皮肤角质层的阻挡作用，使有效成分传导效率低，大部分有效成分仍保留在皮肤表面，难以渗透至皮下。而常见的透皮给药方式，有的装置体积过大、使用不便捷，有的工艺过复杂，有的静电场作用不明显。Drugs applied on the surface of the skin are conducted to the inside of the skin through natural penetration, but due to the barrier effect of the stratum corneum of the skin, the conduction efficiency of the active ingredients is low, and most of the active ingredients remain on the surface of the skin, making it difficult to penetrate into the subcutaneous area. In common transdermal drug delivery methods, some devices are too bulky and inconvenient to use, some have too complicated a process, and some have insignificant electrostatic field effects.
CN105457151A公开了一种超声波及静电复合烧伤膏透皮给药工艺。该工艺中使用一贮库型贴剂主体，包括由外及内依次排布的背衬层、烧伤膏层和托玛琳粉末层，还包括采用驻极体材料制成的驻极体层和控释膜层；所述驻极体层位于背衬层外，控释膜层位于烧伤膏层和托玛琳粉末层之间；所述贮库型贴剂主体还包括一超声波发生层，超声波发生层位于烧伤膏层两侧，并将烧伤膏层夹紧。给药时，首先将贮库型贴剂主体固定在皮肤的烧伤部位上；然后将超声波发生层连接一超声波发生电路，产生超声波，超生波作用于烧伤膏层以及位于烧伤膏层内侧的控释膜层、托玛琳粉末层、皮肤的烧伤部位。该发明所述的透皮给药工艺较复杂，而且驻极体层与直接作用于烧伤皮肤的药物层之间还有背衬层、烧伤膏药层、控释膜层等，驻极体促进药物分子吸收的作用会很弱。CN105457151A discloses a process for transdermal administration of ultrasonic and electrostatic combined burn ointment. In this process, a reservoir-type patch body is used, including a backing layer, a burn ointment layer and a tourmaline powder layer arranged sequentially from the outside to the inside, and also includes an electret layer made of electret material and a Controlled-release film layer; the electret layer is located outside the backing layer, and the controlled-release film layer is located between the burn ointment layer and the tourmaline powder layer; the main body of the storage-type patch also includes an ultrasonic wave generation layer, and the ultrasonic wave The occurrence layer is located on both sides of the burn cream layer and clamps the burn cream layer. When administering medicine, first fix the main body of the reservoir-type patch on the burned part of the skin; then connect the ultrasonic generating layer to an ultrasonic generating circuit to generate ultrasonic waves, and the ultrasonic waves act on the burn cream layer and the controlled release agent located inside the burn cream layer. Film layer, tourmaline powder layer, burnt part of the skin. The transdermal drug delivery process described in this invention is relatively complicated, and there are backing layer, burn plaster layer, controlled release film layer, etc. between the electret layer and the drug layer directly acting on the burned skin. Molecular absorption will be weak.
CN106074460A公开了一种驻极体与5-氟尿嘧啶联合抑制增生性瘢痕生长的透皮给药制剂。该发明所提出的透皮给药制剂，包括一背衬层，背衬层内侧设置有含药压敏胶层，背衬层的外侧设有一采用驻极体材料制成的驻极体层，驻极体层、背衬层、含药压敏胶层形成一贮库型贴剂。驻极体层设有一电能输入端，电能输入端链接一微型处理器系统，微型处理器系统连接一时间模块。该发明通过驻极体可以改变贴剂的粘度和药物的极化参数，调控药物的释放。不过该发明中所述基于微型处理器系统的反馈系统，会使得该透皮给药制剂的尺寸过大，使用的便捷性受到影响。CN106074460A discloses a transdermal preparation for inhibiting hypertrophic scar growth in combination with electret and 5-fluorouracil. The transdermal drug delivery preparation proposed by this invention includes a backing layer, the inner side of the backing layer is provided with a drug-containing pressure-sensitive adhesive layer, and the outer side of the backing layer is provided with an electret layer made of electret material, The electret layer, the backing layer, and the drug-containing pressure-sensitive adhesive layer form a storage-type patch. The electret layer is provided with an electric energy input end, and the electric energy input end is connected with a microprocessor system, and the microprocessor system is connected with a time module. The invention can change the viscosity of the patch and the polarization parameters of the drug through the electret to regulate the release of the drug. However, the feedback system based on the microprocessor system described in this invention will make the size of the transdermal drug delivery preparation too large, and the convenience of use will be affected.
CN109718465A公开了一种3D打印驻极体微针促吸收面膜，包括3D打印的面膜层，面膜层内含有护肤有效成分的基质，面膜层的下表面覆盖有微针阵列层；微针阵列层包括用于固定微针的基层，基层上等间距的固定有中空的微针，微针的中空部分形成给药通道，给药通道的上端刺入面膜层内，下端朝外；面膜层的上表面上覆盖有隔离层，隔离层的上表面上覆盖有驻极体层。该发明在面膜层上，增设了驻极体层和微针层，可利用驻极体产生的微电流和静电场，促进基质向皮肤内层渗透。该发明中通过微型处理器系统连接驻极体层外侧的金属电极层，实现对驻极体内静电场与微电流的控制。由于微型处理器系统输出的控制电压无法达到驻极体的极化电压，很难有效实现对驻极体内静电场与微电流的调控。CN109718465A discloses a 3D printing electret microneedle to promote absorption mask, including a 3D printed mask layer, the mask layer contains a matrix of skin care active ingredients, the lower surface of the mask layer is covered with a microneedle array layer; the microneedle array layer includes The base layer used to fix the microneedles, the base layer is fixed with hollow microneedles at equal intervals, the hollow part of the microneedles forms a drug delivery channel, the upper end of the drug delivery channel penetrates into the mask layer, and the lower end faces outward; the upper surface of the mask layer The top is covered with an isolation layer, and the upper surface of the isolation layer is covered with an electret layer. In this invention, an electret layer and a microneedle layer are added on the mask layer, and the micro-current and electrostatic field generated by the electret can be used to promote the penetration of the matrix into the inner layer of the skin. In this invention, a microprocessor system is used to connect the metal electrode layer outside the electret layer to realize the control of the electrostatic field and microcurrent in the electret. Because the control voltage output by the microprocessor system cannot reach the polarization voltage of the electret, it is difficult to effectively regulate the electrostatic field and micro-current in the electret.
压电驻极体（Piezoelectret）是一种灵敏系数高、柔性良好的新型换能材料，具有良好的柔性和压电效应，且不受热释电效应影响，能将微弱力变化信号转换成电流脉冲。压电驻极体可通过孔洞结构处理、极化等流程制备，常用于高灵敏度力传感器、振动传感器、能量采集器等。Piezoelectret (Piezoelectret) is a new type of transducing material with high sensitivity coefficient and good flexibility. It has good flexibility and piezoelectric effect, and is not affected by pyroelectric effect. It can convert weak force change signals into current pulses . Piezoelectric electrets can be prepared through processes such as pore structure treatment and polarization, and are often used in high-sensitivity force sensors, vibration sensors, energy harvesters, etc.
因此，本领域可利用压电驻极体制备一种体积较小、使用便捷且工艺简单的药物贴剂，以提高经皮给药的药物吸收率。Therefore, piezoelectric electrets can be used in the field to prepare a drug patch with small volume, convenient use and simple process, so as to improve the drug absorption rate of transdermal administration.
技术问题technical problem
针对现有技术存在的不足，本发明的目的在于提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂及其制备方法和应用。所述压电驻极体给药贴剂，通过触压或拍打促进透皮给药，使用方法简单且易于制备，具有较好的应用前景。In view of the deficiencies in the prior art, the purpose of the present invention is to provide a piezoelectric electret drug delivery patch combined with touch pressure or tap transdermal drug delivery, its preparation method and application. The piezoelectric electret drug delivery patch promotes transdermal drug delivery by touching or tapping, has a simple use method and is easy to prepare, and has good application prospects.
技术解决方案technical solution
为达此目的，本发明采用以下技术方案：For reaching this purpose, the present invention adopts following technical scheme:
第一方面，本发明提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂，包括依次层叠设置的覆盖层、压电驻极体层和药物层；所述压电驻极体层包括压电驻极体和与所述压电驻极体结合的金属电极。In the first aspect, the present invention provides a piezoelectret drug delivery patch combined with touch pressure or tap transdermal administration, which includes a covering layer, a piezoelectret layer and a drug layer that are sequentially stacked; The electroelectret layer includes a piezoelectric electret and a metal electrode combined with the piezoelectric electret.
本发明中，所述压电驻极体是透皮给药贴剂中的关键组成。压电驻极体是一种基于聚合物空间电荷驻极体的新型压电材料，具有良好的柔性和压电效应，且不受热释电效应影响；在压电驻极体的表面设置金属电极，所述金属电极为压电驻极体中的电偶极子提供补偿电荷；当压电驻极体在其垂直方向上受到外力触压或拍打时，其内部孔洞结构被压缩，内部电偶极子的偶极矩减小，金属电极中的补偿电荷也相应减小，因此，金属电极中会产生变化的电荷信号，由此可产生微电流脉冲。In the present invention, the piezoelectric electret is a key component in the transdermal drug delivery patch. Piezoelectric electret is a new type of piezoelectric material based on polymer space charge electret, which has good flexibility and piezoelectric effect, and is not affected by pyroelectric effect; metal electrodes are set on the surface of piezoelectric electret , the metal electrode provides compensation charges for the electric dipole in the piezoelectric electret; when the piezoelectric electret is pressed or tapped by an external force in its vertical direction, its internal pore structure is compressed, and the internal electric dipole As the dipole moment of the pole decreases, the compensation charge in the metal electrode also decreases accordingly. Therefore, a changing charge signal will be generated in the metal electrode, thereby generating a microcurrent pulse.
所述结合触压或拍打透皮给药的压电驻极体给药贴剂在使用过程中，触压或拍打压电驻极体而产生的力使其金属电极中产生微电流脉冲，皮肤角质层中的角蛋白在微电流脉冲作用下，由α-螺旋结构的多肽肽链摆成平行排列的多肽肽链，其邻近偶极子之间的相互排斥，导致角质层细胞间质产生新的缺损，改变了角质层层状类脂的排列结构，从而提高皮肤类脂的流动性，扩大了药物分子进入穿透皮肤角质层的通道，有利于药物的经皮渗透。During the use of the piezoelectric electret drug delivery patch combined with touching or tapping for transdermal administration, the force generated by touching or tapping the piezoelectric electret will cause microcurrent pulses to be generated in the metal electrodes, and the skin will Under the action of microcurrent pulses, the keratin in the stratum corneum forms polypeptide chains arranged in parallel by the polypeptide chains of α-helical structure, and the mutual repulsion between the adjacent dipoles leads to the generation of new cells in the interstitial cells of the stratum corneum. The defect of the skin changes the arrangement structure of the stratum corneum lamellar lipids, thereby improving the fluidity of skin lipids, expanding the channels for drug molecules to enter and penetrate the stratum corneum of the skin, and facilitating the percutaneous penetration of drugs.
其中，触压或拍打压电驻极体的方式不限，触压或拍打压电驻极体的力度、频率等根据实际使用情况确定；触压或拍打压电驻极体的具体时长根据药物层的药物成分及其使用方法来确定。Among them, the method of touching or tapping the piezoelectric electret is not limited, and the strength and frequency of touching or tapping the piezoelectric electret are determined according to the actual use; the specific duration of touching or tapping the piezoelectric electret depends on the drug. The drug composition of the layer and its method of use are determined.
本发明中，具体的触压力大小和触压时间，需要根据压电驻极体的灵敏度系数d 33来确定，灵敏度系数d 33越小，所需的触压力越大、触压时间越长。 In the present invention, the specific touch pressure and touch time need to be determined according to the sensitivity coefficient d33 of the piezoelectric electret, the smaller the sensitivity coefficient d33 , the greater the required touch force and the longer the touch time.
作为本发明优选的技术方案，所述金属电极设置于所述压电驻极体与药物层之间。As a preferred technical solution of the present invention, the metal electrode is arranged between the piezoelectric electret and the drug layer.
优选地，所述金属电极的面积小于等于所述压电驻极体的面积。Preferably, the area of the metal electrode is smaller than or equal to the area of the piezoelectric electret.
优选地，所述覆盖层的面积大于所述压电驻极体层的面积。Preferably, the covering layer has an area larger than that of the piezoelectric electret layer.
本发明中所述覆盖层有利于保护压电驻极体层，且覆盖层的面积大于压电驻极体层并与皮肤接触；若压电驻极体厚度较大，其上可不用放置覆盖层，直接在压电驻极体没有镀金属电极的一面进行触压或拍打。The cover layer described in the present invention is beneficial to protect the piezoelectric electret layer, and the area of the cover layer is larger than the piezoelectric electret layer and is in contact with the skin; if the piezoelectric electret is thicker, it is not necessary to place a cover Layer, touch or tap directly on the side of the piezoelectric electret that is not plated with metal electrodes.
作为本发明优选的技术方案，所述压电驻极体层的厚度包括但不限于10μm~1000 μm，例如可以是10μm、20μm、30μm、50μm、80μm、100μm、150μm、200μm、250μm、280μm、300μm、350μm、400μm、450μm、500μm、550μm、600μm、650μm、700μm、750μm、800μm、850μm、900μm、950μm或1000μm等，具体厚度可根据所用驻极体材料性能确定。As a preferred technical solution of the present invention, the thickness of the piezoelectric electret layer includes but is not limited to 10 μm~1000 μm, such as 10 μm, 20 μm, 30 μm, 50 μm, 80 μm, 100 μm, 150 μm, 200 μm, 250 μm, 280 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 8000 μm, 8500 μm , 950μm or 1000μm, etc. The specific thickness can be determined according to the properties of the electret material used.
本发明所述压电驻极体的面积可根据实际透皮给药面积确定。The area of the piezoelectric electret in the present invention can be determined according to the actual transdermal administration area.
优选地，所述压电驻极体采用的聚合物材料可以是具有较好生物相容性的材料，包括但不限于聚丙烯（PP）、氟化乙丙烯聚物（FEP）、聚四氟乙烯（PTFE）、全氟烷氧基树脂（PFA）、聚三氟氯乙烯（PCTFE）、聚偏氟乙烯（PVDF）或聚萘二甲酸乙二醇酯（PEN）中的任意一种或至少两种的组合。Preferably, the polymer material used in the piezoelectric electret can be a material with good biocompatibility, including but not limited to polypropylene (PP), fluorinated ethylene propylene polymer (FEP), polytetrafluoroethylene Any one of ethylene (PTFE), perfluoroalkoxy resin (PFA), polychlorotrifluoroethylene (PCTFE), polyvinylidene fluoride (PVDF) or polyethylene naphthalate (PEN) or at least A combination of the two.
优选地，形成所述金属电极的金属为金（Au）和/或银（Ag）。Preferably, the metal forming the metal electrode is gold (Au) and/or silver (Ag).
本发明中，所述金属电极位于压电驻极体表面，可通过磁控溅射、化学气相沉积等镀膜工艺将其镀在压电驻极体表面，镀膜所用金属为对人体无害的金属，包括但不限于金或银等金属；同时，所述金属电极设置于所述压电驻极体与药物层之间。In the present invention, the metal electrode is located on the surface of the piezoelectric electret, and can be plated on the surface of the piezoelectric electret by magnetron sputtering, chemical vapor deposition and other coating processes, and the metal used for the coating is a metal that is harmless to the human body. , including but not limited to metals such as gold or silver; meanwhile, the metal electrode is arranged between the piezoelectric electret and the drug layer.
优选地，所述金属电极的厚度包括但不限于10 nm~1000 nm，例如可以是10μm、20μm、30μm、50μm、80μm、100μm、150μm、200μm、250μm、280μm、300μm、350μm、400μm、450μm、500μm、550μm、600μm、650μm、700μm、750μm、800μm、850μm、900μm、950μm或1000μm等，具体厚度可根据所用驻极体材料性能确定。Preferably, the thickness of the metal electrode includes but is not limited to 10 nm to 1000 nm, for example, 10 μm, 20 μm, 30 μm, 50 μm, 80 μm, 100 μm, 150 μm, 200 μm, 250 μm, 280 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500μm, 550μm, 600μm, 650μm, 700μm, 750μm, 800μm, 850μm, 900μm, 950μm or 1000μm, etc. The specific thickness can be determined according to the properties of the electret material used.
本发明中，金属电极的厚度包括但不限于几十纳米到几千纳米，优选为10 nm~1000 nm，例如可以是10 nm、20 nm、50 nm、100 nm、150 nm、200 nm、250 nm、300 nm、350 nm、400 nm、450 nm、500 nm、550 nm、600 nm、650 nm、700 nm、750 nm、800 nm、850 nm、900 nm、950 nm或1000 nm等。In the present invention, the thickness of the metal electrode includes but is not limited to tens of nanometers to several thousand nanometers, preferably 10 nm~1000 nm, such as 10 nm, 20 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm or 1000 nm etc.
作为本发明优选的技术方案，所述药物层由与皮肤接触的、包含药物的医用敷料或者直接涂敷于皮肤上的药物形成；As a preferred technical solution of the present invention, the drug layer is formed by a medical dressing that is in contact with the skin and contains drugs or a drug that is directly applied to the skin;
药物层通过将药膏或药液涂抹在皮肤表面形成，或者通过使用几微米后的医用棉膜等材料浸透药膏或药液后贴敷在皮肤表面形成。实际透皮给药包括但不限于上述方式形成药物层。将压电驻极体的金属电极那面放置在药物层上，使金属电极与药物层或皮肤接触。The drug layer is formed by applying ointment or medicinal solution on the skin surface, or by soaking the ointment or medicinal solution with a few microns of medical cotton film and other materials and sticking it on the skin surface. Actual transdermal administration includes, but is not limited to, the formation of a drug layer in the above-mentioned manner. The metal electrode side of the piezoelectric electret is placed on the drug layer so that the metal electrode is in contact with the drug layer or the skin.
放置在压电驻极体上面的覆盖层使用人体无害的薄膜材料，其厚度不限，其尺寸大于压电驻极体尺寸。The cover layer placed on the piezoelectric electret is made of harmless film material, its thickness is not limited, and its size is larger than that of the piezoelectric electret.
优选地，所述覆盖层与压电驻极体层和皮肤接触，用于覆盖所述压电驻极体。Preferably, the covering layer is in contact with the piezoelectric electret layer and the skin for covering the piezoelectric electret.
第二方面，本发明提供一种如第一方面所述的压电驻极体给药贴剂的制备方法，所述制备方法包括：In a second aspect, the present invention provides a method for preparing the piezoelectric electret drug delivery patch as described in the first aspect, the preparation method comprising:
制备包含压电驻极体和金属电极的压电驻极体层；preparing a piezoelectret layer comprising a piezoelectret and a metal electrode;
分别制备药物层和覆盖层；Prepare the drug layer and the covering layer respectively;
再将所述药物层、压电驻极体层和覆盖层依次组装，得到所述压电驻极体给药贴剂。Then, the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
作为本发明优选的技术方案，所述压电驻极体层上的金属电极通过镀膜法与压电驻极体结合。As a preferred technical solution of the present invention, the metal electrodes on the piezoelectric electret layer are combined with the piezoelectric electret by a coating method.
优选地，所述镀膜法包括磁控溅射法和/或化学气相沉积法。Preferably, the coating method includes magnetron sputtering and/or chemical vapor deposition.
作为本发明优选的技术方案，所述压电驻极体的制备方法包括获取孔洞结构和极化的步骤。As a preferred technical solution of the present invention, the preparation method of the piezoelectric electret includes the steps of obtaining a pore structure and polarization.
优选地，所述孔洞结构的获取方法包括但不限于膨化法、模板法或刻蚀法中的任意一种或至少两种的组合。Preferably, the method for obtaining the pore structure includes, but is not limited to, any one or a combination of at least two of puffing, template or etching.
优选地，所述极化的方法包括但不限于电晕极化法、电子束极化或辐照极化法。Preferably, the polarization method includes but not limited to corona polarization method, electron beam polarization method or radiation polarization method.
作为本发明优选的技术方案，所述制备方法包括如下步骤：As a preferred technical solution of the present invention, the preparation method comprises the following steps:
聚合物材料经过膨化法处理得到孔洞结构，再采用电子束辐照极化法进行极化，得到压电驻极体；The polymer material is processed by the puffing method to obtain a pore structure, and then polarized by the electron beam irradiation polarization method to obtain a piezoelectric electret;
采用磁控溅射法和/或化学气相沉积法将金和/或银镀覆于所述压电驻极体的一侧，形成金属电极，所述金属电极的厚度为10 nm~1000 nm，从而得到包含压电驻极体和金属电极的压电驻极体层；Plating gold and/or silver on one side of the piezoelectric electret by magnetron sputtering and/or chemical vapor deposition to form a metal electrode, the thickness of the metal electrode is 10 nm to 1000 nm nm, thereby obtaining a piezoelectret layer comprising a piezoelectret and a metal electrode;
制备药物层，所述药物层为与皮肤接触的、包含药物的医用敷料；preparing a drug layer, which is a medical dressing that contacts the skin and contains drugs;
制备覆盖层，再将所述药物层、压电驻极体层和覆盖层依次组装，得到所述压电驻极体给药贴剂。The covering layer is prepared, and then the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
本发明中，所述压电驻极体给药贴剂可以按照如下方法进行使用：In the present invention, the piezoelectric electret drug delivery patch can be used according to the following method:
首先，在皮肤上通过涂抹或贴敷的方式设置药物层；First, a drug layer is set on the skin by smearing or sticking;
然后，将压电驻极体镀有金属电极的一面覆盖在药物层上，使金属电极接触到皮肤或药物层，在压电驻极体未镀金属电极的一面放置覆盖层；Then, the side of the piezoelectric electret coated with the metal electrode is covered on the drug layer, so that the metal electrode contacts the skin or the drug layer, and a covering layer is placed on the side of the piezoelectric electret that is not plated with the metal electrode;
之后在覆盖层在触压或拍打压电驻极体；Then touch or tap the piezoelectric electret on the covering layer;
在持续触压或拍打压电驻极体一段时间后，可清理掉贴敷在皮肤上的覆盖层、压电驻极体和药物层等材料。After continuously pressing or patting the piezoelectric electret for a period of time, materials such as the covering layer, piezoelectric electret and drug layer applied on the skin can be cleaned off.
第三方面，本发明提供一种如第一方面所述的压电驻极体给药贴剂在制备透皮给药系统中的应用。In a third aspect, the present invention provides an application of the piezoelectric electret drug delivery patch as described in the first aspect in the preparation of a transdermal drug delivery system.
本发明所述的压电驻极体给药贴剂可以用于伤口较小或疼痛感较弱的场景，比如祛瘀消肿、中医推拿、美容护肤等领域。The piezoelectric electret drug delivery patch of the present invention can be used in scenes with small wounds or weak pain, such as blood stasis and swelling, traditional Chinese medicine massage, beauty and skin care and other fields.
本发明所述的数值范围不仅包括上述列举的点值，还包括没有列举出的上述数值范围之间的任意的点值，限于篇幅及出于简明的考虑，本发明不再穷尽列举所述范围包括的具体点值。The numerical ranges described in the present invention not only include the above-listed point values, but also include any point values between the above-mentioned numerical ranges that are not listed. Due to space limitations and for the sake of simplicity, the present invention will not exhaustively list the ranges. The specific pip value to include.
有益效果Beneficial effect
与现有技术相比，本发明的有益效果为：Compared with prior art, the beneficial effect of the present invention is:
（1）本发明基于压电驻极体提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂，所述给药贴剂包括覆盖层、压电驻极体、金属电极和药物层，在该透皮给药贴剂上触压或拍打，压电驻极体内部孔洞结构被压缩，内部电偶极子的偶极矩减小，金属电极中的补偿电荷也相应减小，从而产生微电流脉冲，皮肤角质层中的角蛋白在微电流脉冲作用下，由α-螺旋结构的多肽肽链摆成平行排列的多肽肽链，其邻近偶极子之间的相互排斥，导致角质层细胞间质产生新的缺损，改变了角质层层状类脂的排列结构，从而提高皮肤类脂的流动性，扩大了药物分子进入穿透皮肤角质层的通道，有利于药物的经皮渗透；(1) Based on the piezoelectric electret, the present invention provides a piezoelectric electret drug delivery patch combined with contact pressure or tap transdermal drug delivery. The drug delivery patch includes a covering layer, a piezoelectric electret, When the metal electrode and the drug layer are touched or tapped on the transdermal drug delivery patch, the internal hole structure of the piezoelectric electret is compressed, the dipole moment of the internal electric dipole is reduced, and the compensation charges in the metal electrode are also reduced. Correspondingly, microcurrent pulses are generated. Under the action of microcurrent pulses, the keratin in the stratum corneum of the skin is arranged in parallel by the polypeptide chains of the α-helical structure. Mutual repulsion, resulting in new defects in the interstitial cells of the stratum corneum, changing the arrangement structure of the stratum corneum lamellar lipids, thereby improving the fluidity of the skin lipids, expanding the channel for drug molecules to penetrate the stratum corneum of the skin, and benefiting Percutaneous penetration of drugs;
（2）本发明中，所述触压或拍打压电驻极体的方式不限，触压或拍打的力度、频率等根据实际使用情况确定，且具体的使用时长根据药物层的药物成分及其使用方法来确定；因此，该压电驻极体给药贴剂的使用限制较小，使用范围较广，适用于制备多种类型的透皮给药系统。(2) In the present invention, the method of touching or tapping the piezoelectric electret is not limited, and the strength and frequency of touching or tapping are determined according to the actual use conditions, and the specific use time depends on the drug composition of the drug layer and Its use method is determined; therefore, the use of the piezoelectric electret drug delivery patch is less restricted and has a wider use range, and is suitable for preparing various types of transdermal drug delivery systems.
附图说明Description of drawings
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。In order to more clearly illustrate the technical solutions in the embodiments of the present application, the accompanying drawings that need to be used in the descriptions of the embodiments or the prior art will be briefly introduced below. Obviously, the accompanying drawings in the following description are only for the present application For some embodiments, those of ordinary skill in the art can also obtain other drawings based on these drawings without any creative effort.
图1为本发明提供的压电驻极体给药贴剂的结构示意图，其中1-覆盖层、2-药物层、3-金属电极、4-压电驻极体。Fig. 1 is a schematic structural diagram of the piezoelectric electret drug delivery patch provided by the present invention, wherein 1 - covering layer, 2 - drug layer, 3 - metal electrode, 4 - piezoelectric electret.
图2为本发明提供的压电驻极体给药贴剂的使用流程图。Fig. 2 is a flow chart of the use of the piezoelectric electret drug delivery patch provided by the present invention.
本发明的实施方式Embodiments of the present invention
下面结合附图并通过具体实施方式来进一步说明本发明的技术方案，但下述的实例仅仅是本发明的简易例子，并不代表或限制本发明的权利保护范围，本发明的保护范围以权利要求书为准。The technical scheme of the present invention will be further described below in conjunction with the accompanying drawings and through specific implementation methods, but the following examples are only simple examples of the present invention, and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is based on rights Requirements shall prevail.
以下实施例中，若无特殊说明，所用试剂及耗材均购自本领域常规试剂厂商；若无特殊说明，所用实验方法和技术手段均为本领域常规的方法和手段。In the following examples, unless otherwise specified, the reagents and consumables used were purchased from conventional reagent manufacturers in the field; unless otherwise specified, the experimental methods and technical means used were conventional methods and means in the field.
本发明提供的结合触压或拍打透皮给药的压电驻极体给药贴剂的结构如图1所示，由覆盖层1、压电驻极体层和药物层2组成；The structure of the piezoelectric electret drug delivery patch combined with contact pressure or tapping transdermal drug delivery provided by the present invention is shown in Figure 1, consisting of a covering layer 1, a piezoelectric electret layer and a drug layer 2;
其中，所述压电驻极体层包括压电驻极体4和镀覆于所述压电驻极体一侧表面的金属电极3。Wherein, the piezoelectric electret layer includes a piezoelectric electret 4 and a metal electrode 3 plated on one side of the piezoelectric electret.
所述压电驻极体给药贴剂的使用流程图如图2所示，具体如下：The flow chart of the use of the piezoelectric electret drug delivery patch is shown in Figure 2, specifically as follows:
S1、在皮肤上通过涂抹或贴敷的方式放置药物层2；S1. Place the drug layer 2 on the skin by smearing or sticking;
S2、再将压电驻极体4镀有金属电极3的一面覆盖在药物层2上，使金属电极3接触到涂抹或者贴敷有药物层2的皮肤上；S2, then cover the side of the piezoelectric electret 4 coated with the metal electrode 3 on the drug layer 2, so that the metal electrode 3 is in contact with the skin coated with or pasted with the drug layer 2;
S3、在压电驻极体4未镀金属电极3的一面放置覆盖层；S3, placing a cover layer on the side of the piezoelectric electret 4 that is not plated with the metal electrode 3;
或者，所述药物层2可以与压电驻极体层同时放置于皮肤表面；Alternatively, the drug layer 2 can be placed on the skin surface simultaneously with the piezoelectric electret layer;
S4、在覆盖层1上触压或拍打皮肤，即拍打压电驻极体4；S4. Touching or patting the skin on the covering layer 1, that is, patting the piezoelectric electret 4;
S5、在持续触压或拍打压电驻极体4一段时间后，可清理到贴敷在皮肤上的覆盖层1、压电驻极体4、药物层2等材料；其中，触压或拍打压电驻极体的具体方式、时长和频率等可根据药物层2的药物成分或实际使用情况进行确定；S5. After continuously pressing or patting the piezoelectric electret 4 for a period of time, the materials such as the covering layer 1, the piezoelectric electret 4, and the drug layer 2 applied on the skin can be cleaned; wherein, the touching or patting The specific method, duration and frequency of the piezoelectric electret can be determined according to the drug composition of the drug layer 2 or the actual use;
在所述透皮给药贴剂在使用过程中，触压或拍打压电驻极体4而产生的力使其金属电极中产生微电流脉冲；皮肤角质层中的角蛋白在微电流脉冲作用下，皮肤类脂的流动性增加，扩大了药物分子进入穿透皮肤角质层的通道，有利于药物的经皮渗透。During the use of the transdermal drug delivery patch, the force generated by touching or tapping the piezoelectric electret 4 causes microcurrent pulses to be generated in the metal electrodes; Under this condition, the fluidity of skin lipids increases, which expands the channel for drug molecules to enter and penetrate the stratum corneum of the skin, which is conducive to the percutaneous penetration of drugs.
本发明中，采用的压电驻极体4为聚丙烯压电驻极体。In the present invention, the piezoelectric electret 4 used is a polypropylene piezoelectric electret.
聚丙烯压电驻极体可以采用如下方法进行制备：Polypropylene piezoelectric electret can be prepared by the following method:
①采用包括但不限于膨化法，将聚丙烯薄膜进行孔洞结构处理，使薄膜内部具有为微孔结构，微孔处理条件可采用但不限于氮气环境下气压2 MPa、温度110℃、时间3 h等条件；①Using including but not limited to puffing method, the polypropylene film is subjected to pore structure treatment, so that the inside of the film has a microporous structure, and the microporous treatment conditions can be used but not limited to the pressure of 2 MPa, the temperature of 110 °C, and the time of 3 h in a nitrogen environment and other conditions;
②使用包括但不限于电晕极化法对具有微孔结构的聚丙烯薄膜进行极化处理，极化条件可采用但不限于针压20 kV、栅压5kV、时间2 min等条件。②Polarize the polypropylene film with microporous structure using corona polarization method, including but not limited to, the polarization conditions can be but not limited to needle pressure 20 kV, grid voltage 5 kV, time 2 min and other conditions.
实施例1Example 1
本实施例提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂，所述压电驻极体给药贴剂包括依次层叠设置的覆盖层1、压电驻极体层和药物层2。This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
所述压电驻极体层采用的压电驻极体4为聚丙烯压电驻极体；The piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret;
采用化学气相沉积法将银镀覆于所述压电驻极体4的一侧表面，得到压电驻极体层；Plating silver on one side surface of the piezoelectric electret 4 by chemical vapor deposition to obtain a piezoelectric electret layer;
所述压电驻极体层的厚度为200 μm，其中金属电极3的平均厚度为400 nm，所述金属电极3的面积小于所述压电驻极体4的面积；The thickness of the piezoelectric electret layer is 200 μm, wherein the average thickness of the metal electrode 3 is 400 nm, and the area of the metal electrode 3 is smaller than the area of the piezoelectric electret 4;
所述药物层2为浸透药膏的医用纱布，所述覆盖层1为医用绷带，所述覆盖层1的面积大于所述压电驻极体层的面积；The drug layer 2 is medical gauze soaked in ointment, the covering layer 1 is a medical bandage, and the area of the covering layer 1 is larger than the area of the piezoelectric electret layer;
所述压电驻极体给药贴剂可根据实际所需面积进行裁剪。The piezoelectric electret drug delivery patch can be cut according to the actual required area.
实施例2Example 2
本实施例提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂，所述压电驻极体给药贴剂包括依次层叠设置的覆盖层1、压电驻极体层和药物层2。This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
所述压电驻极体层采用的压电驻极体4为聚丙烯压电驻极体；The piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret;
采用磁控溅射法将银镀覆于所述压电驻极体4的一侧表面，得到压电驻极体层；Plating silver on one side surface of the piezoelectric electret 4 by magnetron sputtering to obtain a piezoelectric electret layer;
所述压电驻极体层的厚度为500 μm，其中金属电极3的平均厚度为100 nm，所述金属电极3的面积小于等于所述压电驻极体4的面积；The thickness of the piezoelectric electret layer is 500 μm, wherein the average thickness of the metal electrode 3 is 100 nm, and the area of the metal electrode 3 is less than or equal to the area of the piezoelectric electret 4;
所述药物层2为浸透药膏的医用纱布，所述覆盖层1为医用绷带，所述覆盖层1的面积大于所述压电驻极体层的面积；The drug layer 2 is medical gauze soaked in ointment, the covering layer 1 is a medical bandage, and the area of the covering layer 1 is larger than the area of the piezoelectric electret layer;
所述压电驻极体给药贴剂可根据实际所需面积进行裁剪。The piezoelectric electret drug delivery patch can be cut according to the actual required area.
实施例3Example 3
本实施例提供一种结合触压或拍打透皮给药的压电驻极体给药贴剂，所述压电驻极体给药贴剂包括依次层叠设置的覆盖层1、压电驻极体层和药物层2。This embodiment provides a piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery. Body layer and drug layer2.
所述压电驻极体层采用的压电驻极体4为聚丙烯压电驻极体；The piezoelectric electret 4 adopted in the piezoelectric electret layer is a polypropylene piezoelectric electret;
采用化学气相沉积法将金镀覆于所述压电驻极体的一侧表面，得到压电驻极体层；plating gold on one surface of the piezoelectric electret by chemical vapor deposition to obtain a piezoelectric electret layer;
所述压电驻极体层的厚度为20 μm，其中金属电极3的平均厚度为50 nm，所述金属电极3的面积小于所述压电驻极体4的面积；The thickness of the piezoelectric electret layer is 20 μm, wherein the average thickness of the metal electrode 3 is 50 nm, and the area of the metal electrode 3 is smaller than the area of the piezoelectric electret 4;
所述药物层2并非为浸透药膏的医用纱布，而是直接涂抹在皮肤表面的药物；所述覆盖层1为医用绷带。The drug layer 2 is not a medical gauze soaked in ointment, but a drug directly applied on the skin surface; the covering layer 1 is a medical bandage.
实施例4Example 4
本实施例提供一种压电驻极体给药贴剂的使用方法，所述使用方法包括如下步骤：This embodiment provides a method for using a piezoelectric electret drug delivery patch, the method for using includes the following steps:
（1）将浸透药膏的医用纱布以贴敷的方式敷于皮肤表面；(1) Apply the medical gauze soaked in the ointment to the surface of the skin by sticking;
（2）将压电驻极体层镀有金属电极3的一面覆盖在医用纱布上，使金属电极3接触到医用纱布；(2) Cover the side of the piezoelectric electret layer coated with the metal electrode 3 on the medical gauze, so that the metal electrode 3 contacts the medical gauze;
（3）在压电驻极体未镀金属电极的一面放置医用绷带，作为覆盖层1，同时固定所述药物层2和压电驻极体层；(3) Place a medical bandage on the side of the piezoelectric electret that is not plated with metal electrodes as the covering layer 1, and fix the drug layer 2 and the piezoelectric electret layer at the same time;
（4）持续拍打压电驻极体20 min后，清理掉贴敷在皮肤上的覆盖层1、压电驻极体层和药物层2。(4) After continuously tapping the piezoelectric electret for 20 minutes, clean off the covering layer 1, piezoelectric electret layer and drug layer 2 that are applied to the skin.
实施例5Example 5
本实施例提供一种压电驻极体给药贴剂的使用方法，所述使用方法包括如下步骤：This embodiment provides a method for using a piezoelectric electret drug delivery patch, the method for using includes the following steps:
（1）将药膏直接涂抹在皮肤表面；(1) Apply the ointment directly on the skin surface;
（2）将压电驻极体层镀有金属电极3的一面覆盖在涂抹药物的皮肤表面，使金属电极3接触到皮肤；(2) Cover the side of the piezoelectric electret layer coated with the metal electrode 3 on the surface of the skin where the drug is applied, so that the metal electrode 3 touches the skin;
（3）在压电驻极体4未镀金属电极3的一面放置医用绷带，作为覆盖层1，同时固定所述压电驻极体层；(3) Place a medical bandage on the side of the piezoelectric electret 4 that is not plated with the metal electrode 3 as the covering layer 1, and fix the piezoelectric electret layer at the same time;
（4）持续触压压电驻极体4三十分钟后，清理掉贴敷在皮肤上的覆盖层、压电驻极体和药物。(4) After continuously touching the piezoelectric electret 4 for 30 minutes, clean off the covering layer, piezoelectric electret and medicine applied on the skin.
其中，实施例4和实施例5中拍打或者触压所使用的力由现有的拍打或者触压装置提供，拍打或者触压提供的力为均匀可控的力。Wherein, the force used for tapping or touching in Embodiment 4 and Embodiment 5 is provided by an existing tapping or touching device, and the force provided by tapping or touching is a uniform and controllable force.
对比例1Comparative example 1
与实施例1的区别仅在于，本对比例中压电驻极体给药贴剂中不放置压电驻极体层，只有覆盖层1和药物层2。The only difference from Example 1 is that in this comparative example, no piezoelectric electret layer is placed in the piezoelectric electret drug delivery patch, only the covering layer 1 and the drug layer 2 .
检测结果Test results
压电驻极体对动态力的检测具有较高的灵敏性，用1~10 N的力触压压电驻极体，压电驻极体最大能输出几百微安级别的电流，能对皮肤有直接的电流刺激效果。The piezoelectric electret has high sensitivity to the detection of dynamic force. When the piezoelectric electret is touched with a force of 1-10 N, the piezoelectric electret can output a current of several hundred microamperes at most, which can The skin has a direct electrical stimulation effect.
实验数据表明，压电系数 d 33为155 pC/N的聚丙烯压电驻极体在10 N的力触压下，输出的刺激电流最大达500 μA。压电驻极体给药贴剂贴在皮肤上，触压一段时间后，检测皮肤中药物分子的浓度。 The experimental data show that the polypropylene piezoelectric electret with a piezoelectric coefficient d 33 of 155 pC/N can output a stimulation current of up to 500 μA under a contact force of 10 N. Piezoelectric electret drug delivery patches are pasted on the skin, and the concentration of drug molecules in the skin is detected after being pressed for a period of time.
实验结果显示，按照实施例4的使用方法使用实施例1~3提供的压电驻极体给药贴剂，实施例1~3的皮肤中药物分子浓度比对比例1中至少高2.3倍以上，这表明在压电驻极体层的作用下，皮肤吸收药物分析的浓度明显提高；The experimental results show that the piezoelectric electret drug delivery patch provided in Examples 1-3 is used according to the method of Example 4, and the concentration of drug molecules in the skin of Examples 1-3 is at least 2.3 times higher than that in Comparative Example 1. , which indicated that under the action of the piezoelectric electret layer, the concentration of the skin-absorbed drug analysis was significantly increased;
实验结果还显示，实施例3的皮肤中药物分子浓度比实施例1和实施例2至少高1.2倍以上，这是由于厚度小的压电驻极体触压时能释放更大的刺激电流，从而使得压电驻极体给药贴剂对促进皮肤吸收药物分子有更明显的效果。The experimental results also show that the concentration of drug molecules in the skin of Example 3 is at least 1.2 times higher than that of Example 1 and Example 2. This is due to the fact that the piezoelectric electret with a small thickness can release a larger stimulating current when it is pressed. Therefore, the piezoelectric electret drug delivery patch has a more obvious effect on promoting skin absorption of drug molecules.
申请人声明，以上所述仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，所属技术领域的技术人员应该明了，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，均落在本发明的保护范围和公开范围之内。The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, and those skilled in the art should understand that any person skilled in the art should be aware of any disclosure in the present invention Within the technical scope, easily conceivable changes or substitutions all fall within the scope of protection and disclosure of the present invention.

Claims (10)

  1. 一种结合触压或拍打透皮给药的压电驻极体给药贴剂，其特征在于，所述压电驻极体给药贴剂包括依次层叠设置的覆盖层、压电驻极体层和药物层；A piezoelectric electret drug delivery patch combined with contact pressure or tapping for transdermal drug delivery, characterized in that the piezoelectric electret drug delivery patch includes a covering layer, a piezoelectric electret layer and drug layer;
    所述压电驻极体层包括压电驻极体和与所述压电驻极体结合的金属电极。The piezoelectric electret layer includes a piezoelectric electret and a metal electrode combined with the piezoelectric electret.
  2. 根据权利要求1所述的压电驻极体给药贴剂，其特征在于，所述金属电极设置于所述压电驻极体与药物层之间；The piezoelectric electret drug delivery patch according to claim 1, wherein the metal electrode is arranged between the piezoelectric electret and the drug layer;
    优选地，所述金属电极的面积小于等于所述压电驻极体的面积；Preferably, the area of the metal electrode is less than or equal to the area of the piezoelectric electret;
    优选地，所述覆盖层的面积大于所述压电驻极体层的面积。Preferably, the covering layer has an area larger than that of the piezoelectric electret layer.
  3. 根据权利要求1或2所述的压电驻极体给药贴剂，其特征在于，所述压电驻极体层的厚度为10μm~1000 μm；The piezoelectric electret drug delivery patch according to claim 1 or 2, wherein the piezoelectric electret layer has a thickness of 10 μm to 1000 μm. μm;
    优选地，所述压电驻极体采用的聚合物材料包括聚丙烯、氟化乙烯离聚物、聚四氟乙烯、全氟烷氧基树脂、聚三氟氯乙烯、聚偏氟乙烯或聚萘二甲酸乙二醇酯中的任意一种或至少两种的组合。Preferably, the polymer material used in the piezoelectric electret includes polypropylene, fluorinated vinyl ionomer, polytetrafluoroethylene, perfluoroalkoxy resin, polychlorotrifluoroethylene, polyvinylidene fluoride or polyvinylidene fluoride. Any one or a combination of at least two of ethylene naphthalate.
  4. 根据权利要求1~3任一项所述的压电驻极体给药贴剂，其特征在于，形成所述金属电极的金属为金和/或银；The piezoelectric electret drug delivery patch according to any one of claims 1 to 3, wherein the metal forming the metal electrode is gold and/or silver;
    优选地，所述金属电极的厚度为10 nm~1000 nm。Preferably, the metal electrode has a thickness of 10 nm to 1000 nm.
  5. 根据权利要求1~4任一项所述的压电驻极体给药贴剂，所述药物层包括与皮肤接触的、包含药物的医用敷料或者直接涂敷于皮肤上的药物；According to the piezoelectric electret drug delivery patch according to any one of claims 1 to 4, the drug layer includes a medical dressing in contact with the skin, containing a drug or a drug directly applied to the skin;
    优选地，所述覆盖层与压电驻极体层和皮肤接触，用于覆盖所述压电驻极体。Preferably, the covering layer is in contact with the piezoelectric electret layer and the skin for covering the piezoelectric electret.
  6. 一种如权利要求1~5任一项所述的压电驻极体给药贴剂的制备方法，其特征在于，所述制备方法包括：A preparation method of the piezoelectric electret drug delivery patch according to any one of claims 1 to 5, wherein the preparation method comprises:
    制备包含压电驻极体和金属电极的压电驻极体层；preparing a piezoelectret layer comprising a piezoelectret and a metal electrode;
    分别制备药物层和覆盖层；Prepare the drug layer and the covering layer respectively;
    再将所述药物层、压电驻极体层和覆盖层依次组装，得到所述压电驻极体给药贴剂。Then, the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
  7. 根据权利要求6所述的制备方法，其特征在于，所述压电驻极体层上的金属电极通过镀膜法与压电驻极体结合；The preparation method according to claim 6, wherein the metal electrode on the piezoelectric electret layer is combined with the piezoelectric electret by a coating method;
    优选地，所述镀膜法包括磁控溅射法和/或化学气相沉积法。Preferably, the coating method includes magnetron sputtering and/or chemical vapor deposition.
  8. 根据权利要求6或7所述的制备方法，其特征在于，所述压电驻极体的制备方法包括获取孔洞结构和极化的步骤；The preparation method according to claim 6 or 7, characterized in that, the preparation method of the piezoelectric electret comprises the steps of obtaining pore structure and polarization;
    优选地，所述孔洞结构的获取方法包括膨化法、模板法或刻蚀法中的任意一种或至少两种的组合；Preferably, the method for obtaining the pore structure includes any one or a combination of at least two of the expansion method, template method or etching method;
    优选地，所述极化的方法包括电晕极化法、电子束极化或辐照极化法。Preferably, the polarization method includes corona polarization method, electron beam polarization method or radiation polarization method.
  9. 根据权利要求6~8任一项所述的制备方法，其特征在于，所述制备方法包括如下步骤：The preparation method according to any one of claims 6 to 8, wherein the preparation method comprises the steps of:
    聚合物材料经过膨化法处理得到孔洞结构，再采用电子束辐照极化法进行极化，得到压电驻极体；The polymer material is processed by the puffing method to obtain a pore structure, and then polarized by the electron beam irradiation polarization method to obtain a piezoelectric electret;
    采用磁控溅射法和/或化学气相沉积法将金和/或银镀覆于所述压电驻极体的一侧，形成金属电极，所述金属电极的厚度为10 nm~1000 nm，从而得到包含压电驻极体和金属电极的压电驻极体层；Plating gold and/or silver on one side of the piezoelectric electret by magnetron sputtering and/or chemical vapor deposition to form a metal electrode, the thickness of the metal electrode is 10 nm to 1000 nm nm, thereby obtaining a piezoelectret layer comprising a piezoelectret and a metal electrode;
    制备药物层，所述药物层为与皮肤接触的、包含药物的医用敷料；preparing a drug layer, which is a medical dressing that contacts the skin and contains drugs;
    制备覆盖层，再将所述药物层、压电驻极体层和覆盖层依次组装，得到所述压电驻极体给药贴剂。The covering layer is prepared, and then the drug layer, the piezoelectric electret layer and the covering layer are sequentially assembled to obtain the piezoelectric electret drug delivery patch.
  10. 如权利要求1~5任一项所述的压电驻极体给药贴剂在制备透皮给药系统中的应用。Application of the piezoelectric electret drug delivery patch as described in any one of claims 1 to 5 in the preparation of a transdermal drug delivery system.
PCT/CN2021/137768 2021-08-26 2021-12-14 Piezoelectret drug delivery patch in combination with transdermal drug delivery by means of pressing or patting, and preparation method therefor and application thereof WO2023024338A1 (en)

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