Method of treating skin to homeostasis with dosing facilitated

Abstract

The present application belongs to the technical field of transdermal dosing, and particularly relates to a method for treating skin to steady state for facilitating dosing, which comprises the following steps: providing a microneedle device or a nanocrystal sheet; performing a dredging treatment operation on a skin surface by the microneedle device or the nanocrystal sheet, the dredging treatment operation comprising reciprocating point treatment in a direction perpendicular to the skin surface and / or sliding treatment along the skin surface; and the dredging treatment operation lasts for a specific time length to achieve that the skin surface is dredged to steady state. The present application corrects the cognitive error of the industry on microneedle transdermal dosing, overcomes the technical bias of the technical personnel in the field, and the method provided by the present application can make the permeability of the absorption channel of the skin surface reach steady state, thereby providing a basis for transdermal dosing.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of transdermal dosing, in particular to a method for treating skin to steady state for facilitating dosing. BACKGROUND

[0002] Micro-needle transdermal drug delivery technology is one of the innovative technologies that have been developed in recent years. It uses micro-needle units to open channels on the surface of the skin, so that drug ingredients can directly enter the subcutaneous tissue and be absorbed by the human body. This technology has the advantages of safety, high efficiency, painlessness and non-invasiveness. It can effectively improve the absorption efficiency of drug ingredients, reduce the waste of drug ingredients, and reduce the impact of liver first-pass effect. To some extent, it can replace traditional injection drug delivery and has a wide application prospect in many fields such as medical treatment and beauty.

[0003] Traditional micro-needle transdermal drug delivery can efficiently deliver drugs from the skin surface to the body, but it cannot achieve the quantitative input of drug dosage. Some research institutions have tried to control the quantitative input of drugs in the following ways: setting a drug coating on the surface of the micro-needle unit, or setting a drug storage tank on the micro-needle unit, and pre-storing a certain amount of drug in the drug storage tank. However, in actual experiments, due to the small size of the micro-needle unit (micron or even nanometer), it is very difficult to set a drug storage tank or a drug coating on the micro-needle unit. Therefore, although the above methods can achieve quantitative drug delivery to some extent, they greatly increase the manufacturing difficulty and production cost of the micro-needle unit, which is not conducive to the industrialization and popularization of micro-needle transdermal drug delivery. In addition, the amount of drug that can be carried on the surface or inside of the micro-needle unit is very small, which cannot achieve an effective drug dosage in many fields of application. This is also one of the factors restricting the further development and popularization of micro-needle transdermal drug delivery technology. SUMMARY

[0004] In order to solve the technical problem that micro-needle transdermal drug delivery cannot achieve quantitative input, the present application provides a method for treating skin to steady state for facilitating dosing. The method for treating skin to steady state for facilitating dosing comprises the following steps: providing a micro-needle device or a nanocrystal sheet; performing a channeling treatment operation on the skin surface by the micro-needle device or the nanocrystal sheet, the channeling treatment operation comprising reciprocating point lifting treatment along a direction perpendicular to the skin surface, and / or sliding treatment along the skin surface; and the channeling treatment operation lasts for a certain period of time to achieve that the skin surface is channelized to steady state.

[0005] The above technical solution is further described as follows.

[0006] Treatment of skin: The microneedle transdermal drug delivery technology includes two key steps, one of which is to clear the skin area to be administered; the second step is to input drugs to the skin area to be administered. In clinical operation, the two steps can be performed simultaneously or in steps. When one of the steps is performed first, it can be referred to as pre-treatment of the skin; when the second step is performed first, it can be referred to as post-treatment of the skin. The "treatment of skin" in the technical solution of the present application refers to one of the steps, and the specific operation sequence is not limited.

[0007] Microneedle device or nanocrystal sheet: refers to a device including a microneedle unit, which can be one or more of a micro-needle, a micro-blade, and a micro-knife.

[0008] Skin homeostasis: Skin surface permeability: Skin surface permeability refers to the amount of active substance passing through a unit area per unit time. The microneedle unit can clear the skin channel and improve the skin surface permeability; and the longer the microneedle unit acts, the higher the skin surface permeability, and the easier the drug penetrates into the body. This is the industry's consistent understanding. Based on the above industry common sense and the individual skin differences of users, industry experts believe that the clearing effect of the microneedle unit on the skin cannot meet the unified standard, resulting in unstable transdermal absorption of drugs, and thus cannot achieve quantitative drug delivery. The above cognition makes the research direction of the industry focus on soluble microneedles and other microneedle products that can carry a certain amount of drugs. The present applicant accidentally discovered during long-term research and development and service to users that the skin surface permeability tends to be stable after the microneedle unit is operated on the skin for a specific period of time, that is, the skin clearing effect reaches a stable state. After long-term and large-scale clinical experiments, the present applicant found that the skin clearing effect of the microneedle unit has a stable interval, and the skin surface clearing effect tends to be stable after the microneedle unit is operated on the skin for a specific period of time, and no longer significantly improves with the continued action of the microneedle unit. This technology refers to the state in which the skin surface permeability tends to be stable as "skin homeostasis".

[0009] The skin surface permeability and the skin surface transdermal water loss value (TEWL value) have a positive correlation, and when the skin surface permeability increases, the skin surface transdermal water loss value also increases. Therefore, the skin surface transdermal water loss value can be used as one of the indicators to measure the skin clearing effect.

[0010] Specific period of time: The specific period of time refers to the time from the start of the microneedle device or nanocrystal sheet to the skin surface clearing operation to the time when the skin surface clearing effect reaches a stable state.

[0011] The present application uses a microneedle device or a nanocrystal sheet to perform a skin unblocking treatment, and uses a point lifting or sliding unblocking treatment to unblock the channels on the skin surface; as the unblocking treatment is performed, the transdermal water loss value of the skin surface is increased; after a certain duration of continuous operation, the transdermal water loss value of the skin surface tends to be stable and eventually reaches a steady state.

[0012] The method can make the unblocking effect of the skin reach a unified stable state. Based on the stable state, the subsequent variable in the quantitative drug delivery step can be effectively reduced, so that the control of the quantitative drug delivery is simpler and more convenient.

[0013] In the preferred technical scheme of the present application, the initial transdermal water loss value of the skin surface is measured before the step of performing an unblocking treatment on the skin surface by the microneedle device or the nanocrystal sheet. By measuring the initial transdermal water loss value of the skin surface, the initial state of the skin surface of the patient is understood, and data basis is provided for the subsequent determination of the skin surface entering a steady state.

[0014] In the preferred technical scheme of the present application, the step of performing the unblocking treatment for a certain duration to achieve the unblocking of the skin surface to a steady state includes monitoring the transdermal water loss value of the skin surface, and stopping the unblocking treatment when the transdermal water loss value reaches a certain standard value. Through the above configuration, after the transdermal water loss value reaches the certain standard value, the value of the transdermal water loss value changes little with the duration of the unblocking treatment, so as to determine that the skin surface reaches a steady state.

[0015] In the preferred technical scheme of the present application, the certain standard value is that the transdermal water loss value of the skin surface reaches 1.5-6 times the initial transdermal water loss value.

[0016] In the preferred technical scheme of the present application, the microneedle device or the nanocrystal sheet includes a microneedle unit, and the microneedle unit includes one or more of a micro-needle, a micro-blade, and a micro-knife.

[0017] In the preferred technical scheme of the present application, the density of the microneedle unit is 10-1600 per square centimeter.

[0018] In the preferred technical scheme of the present application, the maximum radial dimension of the tip of the microneedle unit is not greater than 50 microns.

[0019] In the preferred technical scheme of the present application, the certain duration is more than 10 seconds.

[0020] In the preferred technical scheme of the present application, the skin surface is one or more of the stratum corneum, the granular layer, the stratum spinosum, and the basal layer of the skin.

[0021] The method for treating skin to homeostasis for facilitating dosing of the present application comprises the following steps: a decongestion treatment operation is performed on the skin surface by a microneedle device or a nanocrystal sheet for a specific duration to achieve that the skin surface is decongested to homeostasis, and the method for treating skin to homeostasis for facilitating dosing is used for non-therapeutic purposes. BRIEF DESCRIPTION OF DRAWINGS

[0022] The preferred embodiments of the present application will be described below with reference to the accompanying drawings, in which:

[0023] Figure 1 is a step diagram of embodiment one of the method for treating skin to homeostasis for facilitating dosing of the present application;

[0024] Figure 2 is a graph of the relationship between the skin's transepidermal water loss value and the duration of the decongestion treatment operation in embodiment one of the method for treating skin to homeostasis for facilitating dosing of the present application. DETAILED DESCRIPTION

[0025] In the field of microneedle transdermal drug delivery technology, a micro device or a nanocrystal sheet performs a decongestion treatment operation on the skin surface in a specific way to form channels on the skin surface and improve the permeability of the skin surface; drug ingredients enter the body from the channels on the skin surface, achieving transdermal drug delivery. This technology can replace injection drug delivery to some extent, but industry experts have always believed that the decongestion treatment effect of the micro device or the nanocrystal sheet on the skin surface cannot be accurately controlled, resulting in that drug ingredients cannot be quantitatively input into the body from the skin surface. This situation seriously hinders the development and popularization of microneedle transdermal drug delivery.

[0026] In the research of this technical problem, the present applicant accidentally found that when the micro device or the nanocrystal sheet performs a decongestion treatment operation on the skin surface, the decongestion effect of the skin surface has a stable interval, that is, after a specific duration of decongestion treatment operation, the permeability and the transepidermal water loss value of the skin surface reach a stable interval. The appearance of this stable interval makes the decongestion effect of the skin surface controllable, measurable, and even accurately assessable, which also provides a basis for quantitative drug delivery.

[0027] Therefore, the present application provides a method for treating skin to homeostasis for facilitating dosing. The method for treating skin to homeostasis for facilitating dosing comprises the following steps: providing a microneedle device or a nanocrystal sheet; performing a decongestion treatment operation on the skin surface by the microneedle device or the nanocrystal sheet, the decongestion treatment operation including reciprocating point treatment in the direction perpendicular to the skin surface, and / or sliding treatment along the skin surface; and the decongestion treatment operation lasts for a specific duration to achieve that the skin surface is decongested to homeostasis.

[0028] The microneedle device or nanocrystal sheet refers to a device with microneedle units, such as a single crystal silicon substrate, and microneedle units arranged in an array on the substrate. The material forming the microneedle unit can be single crystal silicon, metal such as stainless steel, polymer material or other suitable material. It is easy to understand that according to the specific design requirements, the number of microneedle units can be multiple or one. The structure of the microneedle unit can be a micro-needle, a micro-blade, a micro-taper, a micro-knife or other suitable structure. The height of the micro-unit is 10-500 microns. Optionally, the height of the micro-unit is 200 microns. The maximum radial dimension of the micro-unit is not greater than 1 micron, and the size of the tip of the micro-unit is not greater than 500 nanometers. Optionally, the micro-unit is in the form of a micro-needle structure, and the maximum radial dimension at the position connected to the substrate is 1 micron, and the size of the needle tip is less than 100 nanometers. The arrangement density of the micro-unit is 10-1600 per square centimeter. Preferably, the arrangement density of the micro-unit is 100-900 per square centimeter. Optionally, the arrangement density of the micro-unit is 500 per square centimeter.

[0029] The skin from the outside to the inside includes the epidermis, the dermis, and the subcutaneous tissue. The skin surface in the present application refers to one or more of the stratum corneum, the stratum granulosum, the stratum spinosum and the stratum basale of the skin. With different heights of micro-units, different depth layers of the skin surface can be dredged, so as to realize the input of drug components at a certain layer and a certain point.

[0030] In the step of "dredging the skin surface by the microneedle device or nanocrystal sheet", the dredging operation of the present application includes reciprocating point treatment of the microneedle unit in the direction perpendicular to the skin surface; also includes sliding treatment along the skin surface, which can be reciprocating translation sliding or circle drawing sliding; the dredging operation can also combine the above two actions.

[0031] In the initial stage of dredging the skin surface, as the dredging operation proceeds, the permeation amount of the skin surface increases. Taking the transdermal water loss value of the skin surface as the monitoring index, as the dredging operation proceeds, the transdermal water loss value of the skin surface gradually increases. When the dredging operation continues for a certain period of time, the value of the transdermal water loss value no longer increases with the continuous dredging operation, at this time, the transdermal water loss value increases very slowly, and can be considered to be maintained in a stable value range.

[0032] In the step of "continuing the unblocking treatment operation for a specific duration to achieve that the skin surface is unblocked to a steady state", after the skin is unblocked by the microneedle device or the nanocrystal sheet for a specific duration, the skin surface is unblocked to a steady state, and the transdermal water loss value of the skin surface is maintained stable. According to the different requirements of the accuracy of the quantitative administration and other administration requirements, the transdermal water loss value of the skin surface reaching 1.5-6 times of the initial transdermal water loss value can be optionally regarded as that the skin surface enters the steady state. Preferably, the transdermal water loss value of the skin surface reaching 2.4-2.6 times of the initial transdermal water loss value can also be regarded as that the skin surface enters the steady state.

[0033] According to the different standards of the skin entering the steady state, and the different density and size of the microneedle unit selected, the specific duration has different specific numerical ranges. The technical solutions of the present application are further explained below by combining the drawings and through several embodiments.

[0034] Embodiment one

[0035] Figure 1 is a step diagram of embodiment one of the method for treating the skin to a steady state for facilitating the quantitative administration of the present application. As shown in Figure 1 In this embodiment one, the method for treating the skin to a steady state for facilitating the quantitative administration comprises the following steps:

[0036] cleaning the skin surface (step s1);

[0037] measuring the initial transdermal water loss value T1 of the skin surface (step s2);

[0038] providing a nanocrystal sheet, the microneedle units on the nanocrystal sheet are arrayed microneedles, the density of the microneedles is 500 per square centimeter, the height of the microneedles is 200 microns, and the needle tip radius is less than 100 nm (step s3);

[0039] performing the point unblocking treatment operation on the skin surface by the nanocrystal sheet (step s4);

[0040] monitoring the transdermal water loss value T2 of the skin surface (step s5);

[0041] maintaining the point unblocking treatment operation until the transdermal water loss value T2 of the skin surface reaches 2.4 times of the initial transdermal water loss value T1. The unblocking treatment operation is completed (step s6).

[0042] Figure 2 is a graph of the relationship between the transdermal water loss value of the skin and the duration of the unblocking treatment operation in embodiment one of the method for treating the skin to a steady state for facilitating the quantitative administration of the present application. As shown in Figure 2As shown, the initial transdermal water loss value T1 of the skin surface is 12 (g / h*m2), after the skin surface is unblocked for 10s using the nanocrystal sheet, the transdermal water loss value T2 of the skin surface is 29 (g / h*m2), which is 2.4 times the initial transdermal water loss value T1. After continuing to process for 20s, the transdermal water loss value of the skin surface only increases slightly, and the transdermal water loss value tends to be stable, and the corresponding skin surface is unblocked to a steady state. As can be seen, after the skin surface is processed for a certain period of time, the unblocking effect tends to be stable and reaches a steady state.

[0043] Example Two

[0044] Different from Example One, in this Example Two,

[0045] The nanocrystal sheet is used to slide along the skin surface for unblocking processing operation;

[0046] And the sliding unblocking processing operation is maintained until the transdermal water loss value T2 of the skin surface reaches 2.6 times the initial transdermal water loss value T1. The unblocking processing operation is completed.

[0047] Example Three

[0048] Different from Example One, in this Example Three, the point unblocking processing operation is maintained until the transdermal water loss value T2 of the skin surface reaches 2.5 times the initial transdermal water loss value T1. The unblocking processing operation is completed.

[0049] Example Four

[0050] In some use scenarios, the active substance, active substance formula or effective ingredient can be placed on the skin surface first, and then the skin is processed using the method provided in the present application. At this time, during the process of processing the skin using the microneedle device or the nanocrystal sheet, the active substance will be synchronously taken into the deep layer of the skin, thereby realizing the introduction of the effective ingredient while unblocking the skin, and achieving the effect of accelerating absorption.

[0051] So far, the technical solutions of the present application have been described in combination with the preferred embodiments shown in the drawings, but those skilled in the art should understand that the protection scope of the present application is obviously not limited to these specific embodiments, and these embodiments are only used to explain the technical principles of the present application, and are not intended to limit the protection scope of the present application. Without deviating from the principles of the present application, those skilled in the art can make equivalent changes or replacements to related technical features, and the technical solutions after these changes or replacements will fall within the protection scope of the present application.

Claims

1. A method for treating skin to steady state for convenient quantitative drug administration, characterized in that, The method for treating the skin to steady state to facilitate quantitative drug administration includes the following steps: Provide a microneedle device or nanochip; The microneedle device or nanocrystal is used to perform a patting treatment on the skin surface, which includes reciprocating point lifting along a direction perpendicular to the skin surface and / or sliding along the skin surface; the skin surface is the stratum corneum of the skin. The unblocking treatment operation lasts for a specific duration to achieve a steady state on the skin surface, where steady state refers to the stable state of the amount of active substance passing through a unit area of ​​the skin surface per unit time; the method for treating the skin to a steady state for easy quantitative drug administration is used for non-therapeutic purposes.

2. The method for treating skin to steady state for convenient quantitative drug administration according to claim 1, characterized in that, Prior to the step of performing the unblocking treatment on the skin surface using the microneedle device or nanocrystal, the initial transepidermal water loss value of the skin surface is measured.

3. The method for treating skin to steady state for convenient quantitative drug administration according to claim 2, characterized in that, The steps of the unblocking treatment operation, which lasts for a specific duration to achieve a steady state of unblocking on the skin surface, include: The transepidermal water loss value of the skin surface is monitored, and the unblocking treatment operation is stopped when the transepidermal water loss value reaches a specific standard value.

4. The method for treating skin to steady state for convenient quantitative drug administration according to claim 3, characterized in that, The specific standard value is that the transepidermal water loss value of the skin surface reaches 1.5-6 times the initial transepidermal water loss value.

5. The method for treating the skin to steady state for convenient quantitative administration according to any one of claims 1-4, characterized in that, The microneedle device or nanocrystal includes a microneedle unit, which includes one or more of microneedles, microblades, and microknives.

6. The method for treating skin to steady state for convenient quantitative drug administration according to claim 5, characterized in that, The arrangement density of the microneedle unit is 10-1600 needles / square centimeter.

7. The method for treating skin to steady state for convenient quantitative drug administration according to claim 6, characterized in that, The maximum radial dimension of the tip of the microneedle unit is no greater than 50 micrometers.

8. The method for treating skin to steady state for convenient quantitative drug administration according to claim 7, characterized in that, The specified duration is 10 seconds or more.

9. A method for treating skin to steady state for convenient quantitative drug administration, characterized in that, The method for treating the skin to steady state to facilitate quantitative drug administration includes the following steps: The skin surface is unclogged to a steady state by using a microneedle device or nanocrystal to perform a specific duration of unclogging treatment. The skin surface is the stratum corneum of the skin. The steady state refers to the stable state of the amount of active substances passing through a unit area of ​​the skin surface per unit time. The method of treating the skin to a steady state for easy quantitative drug administration is used for non-therapeutic purposes.

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