WO2025141301A1

WO2025141301A1 - Microneedle patch

Info

Publication number: WO2025141301A1
Application number: PCT/IB2023/063263
Authority: WO
Inventors: Supason Wanichwecharungruang; Naruchit THANUTHANAKHUN; Chayanon TIANGTHAM
Original assignee: Mineed Technology Co Ltd
Current assignee: Mineed Technology Co Ltd
Priority date: 2023-12-27
Filing date: 2023-12-27
Publication date: 2025-07-03
Anticipated expiration: 2026-06-27

Abstract

The present invention relates to a microneedle patch comprising a base, which is made of a material having liquid-permeable cavities, and multilayered microneedles, which have a proximal end adjacent to the base and a distal end opposite thereto. The multilayered microneedles comprise a substance containing layer and a penetrating tip disposed at the distal end of the multilayered microneedles. The multilayered microneedles may further comprise a connecting layer and a barrier layer. In some embodiments, the microneedle patch comprises assorted microneedles. The microneedle patch of this invention can prevent microneedles ejection from the skin, minimize reverse flow and prevent unwanted mixing between layers, ensuring efficient delivery while offering customizable options across a spectrum of applications.

Description

MICRONEEDLE PATCH

TECHNICAL FIELD

The present invention relates to a microneedle patch. Specifically, the invention relates to a microneedle patch comprising multilayered microneedles developed to deliver precise amounts of substances to targeted areas effectively. These microneedles can prevent microneedles ejection from the skin, minimize reverse flow and prevent unwanted mixing between layers, ensuring efficient delivery while offering customizable options across a spectrum of applications. In addition, the invention relates to a microneedle patch comprising assorted microneedles arranged on the same patch.

BACKGROUND OF THE INVENTION

Multilayered microneedles have received increasing interest in the past decade, with objectives to precisely deliver more than one substance and control delivery rate. Nevertheless, there remains a challenge especially when the microneedles are short and/or hydrophobic; “bouncing back” or ejection of the microneedles from the skin are often observed. For example, when microneedles are designed to deliver tattoo ink just under the epidermis or cosmetic ingredients to the stratum corneum, the short microneedles do not have sufficient retention in the skin and therefore are ejected out. In addition, there is a need for assorted microneedle patch, where microneedles on the same patch are formed to have variations of structure or material or substance or a combination thereof. However, due to limitations of manufacturing techniques and apparatus, their production has not been a success.

For multilayered microneedles, precise compartmentalization is required. However, to this date, it is still difficult to prevent migration or diffusion of contained substance or components of the microneedles to undesired direction or to prevent unwanted mixing between layers. Unlike the substance that is located at a needle tip which is usually fully embedded in the skin during the application of the microneedles, the substance located at or near the base may flow back to the base or stay on top of the skin. As a result, the amount of substance actually delivered is less than expected and the substance might be delivered to an undesired skin layer.

Another challenge in the art of dissolvable microneedles is that the detachment of the microneedles from the base after applying the microneedle patch to the skin takes a long time. The whole microneedle patch therefore must remain on the skin for a long time, creating pores on the skin which cannot be quickly closed, thus causing damage to the skin and a risk of infection. The base should be able to be removed quickly and effectively, while leaving the microneedles embedded in the skin. Preferably, the rate at which each microneedle is dissolved or degraded in the skin after being embedded should be individually controlled. This will help enhance delivery efficiency especially when each microneedle on the same patch is formed to have different material, solubility rate, substance, and layer structure.

Below, we discuss some patent documents that explore the development of multilayered microneedles for diverse purposes.

KR 102567995 Bl discloses multilayered microneedles comprising a base portion and a tip portion including at least two or more tip sublayers. According to their invention, the active ingredient is either provided to the first tip sublayer (at the distal end) or the second tip sublayer (adjacent to the base) or both. If the active ingredient is required to be released immediately, it will be added to the first tip sublayer; if sustained release is required, it will be added to second tip sublayer, and if both is required, it will be added to both layers. This Korean patent also discloses that since the tip portion includes a plurality of tip portion sublayers, it is possible to provide various drugs or the same drug in various patterns.

WO 2020/043167 Al discloses multilayered microneedles comprising a needle tip, a middle layer, a needle body, and a base, wherein an active ingredient is contained in the tip. The microneedles according to their invention are prepared by injection molding where, after the needle tip injection liquid (containing the active agent) is injected into a mold, it is heated at a temperature of 30-80 30-80 ⁰ C. and the heating time is 1-24 hours. With such high temperature, it will not be suitable for active ingredients which are heat-sensitive such as vaccines or mRNA. In addition, since it can take up to 24 hours to form one layer, it will not be practical to produce microneedles with three or more layers or assorted microneedle patch. Also, there is no means to ensure that the active ingredient will be confined at the tip only without diffusing to an adjacent layer.

WO2017/043627 discloses a microneedle having a first portion which is provided with a top part and includes a water-insoluble biodegradable polymer substance and an object substance dissolved or dispersed in the polymer substance, a second portion which is provided with a base part and includes a water-soluble substance dissolved in a solvent capable of dissolving the water-insoluble biodegradable polymer substance, and a third portion located between the second part and the support. There is no feature indicating the containment of bioactive substances at any of the portions and the prevention of the diffusion of bioactive ingredients between different portions.

Besides the drawbacks discussed above, it can be observed that the prior art documents do not disclose multilayered microneedles with more than three layers or an assorted microneedle patch, where one patch consists of microneedles that are formed to have different material, dissolution rate, substance/active ingredient, or layer structure. It is noteworthy that prevention of “bouncing back” and customization remains a challenge.

SUMMARY OF THE INVENTION

The present invention relates to a microneedle patch. The microneedle patch comprises a base, which is made of a material having liquid-permeable cavities, and multilayered microneedles, which have a proximal end adjacent to the base and a distal end opposite thereto. The multilayered microneedles comprise a substance containing layer and a penetrating tip disposed at the distal end of the multilayered microneedles.

In some embodiments, the multilayered microneedles further comprise a connecting layer connecting a bottom portion of the multilayered microneedles to the base, and/or a barrier layer which helps prevent migration of the substance or components of the microneedles to an undesired direction or undesired mixing between layers.

In further embodiments, the substance containing layer and the connecting layer are made from the same material and are integrally formed.

In yet further embodiments, the microneedle patch comprises assorted microneedles, wherein the microneedles are formed to have variations of structure or material or substance or a combination thereof.

According to the present invention, the penetrating tip does not contain a substance and is disposed at the distal end of the multilayered microneedles. The length of the penetrating tip can be adjusted to match the intended applications. With this penetrating tip, the length/thickness of other layers can be individually varied without affecting the total length of the microneedles. It also enhances retention of the microneedles in the skin after the application, hence preventing the “bouncing back”. This feature of the present invention is especially useful for tattooing and cosmetic applications where the substance will be delivered not so deep in the skin. It allows the substance containing layer to be positioned in the upper skin layer while the penetrating tip securely retains the microneedles in the skin. In order to achieve the skin penetration and retention function, the penetrating tip according to the present invention was tested and designed to withstand certain compressive force. Preferably, the penetrating tip can withstand at least 0.03 N of compressive force/needle. For instance, it can withstand compressive force ranging from 0.03-80 N/needle or 0.05-30 N/needle.

Other than the penetrating tip at the distal end and the connecting layer (if present) at the proximal end of the microneedles, other layers can be arranged as appropriate.

The main objective of the present invention is to provide a microneedle patch comprising microneedles with enhanced skin retention while allowing each layer to be individually tailored. As a result, a more effective delivery of an accurate dosing of each substance can be delivered to a designated skin layer. Further, the assorted microneedles allow customization of a patch to suit intended applications.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a side view of the microneedle patch according to an exemplary embodiment of the present invention.

Fig. 2 shows exemplary embodiments of the tattoo microneedle patch according to the present invention. Fig. 2a illustrates a microneedle patch for temporary tattoo and Fig. 2b illustrates a microneedle patch for permanent tattoo.

Fig. 3 illustrates a mechanical strength testing using a universal testing machine.

Fig. 4 shows how a tattoo patch according to an exemplary embodiment of the present invention can be used.

Figs 5a-5c show exemplary embodiments of the microneedle patch according to the present invention with variations of individual and grouped connecting layer.

Fig. 6 shows physical appearance of an exemplary embodiment of microneedles according to the present invention, that are insulin microneedles of Example 1. Fig. 6a is a stereomicroscopic image of the Lissamine Rhodamine B insulin-loaded multilayered microneedles. Fig. 6b is a fluorescence image of the Lissamine Rhodamine B insulin-loaded multilayered microneedles.

Fig. 7 shows stereomicroscopic images of cross sectioned ex vivo porcine skin after an administration of Lissamine Rhodamine B - insulin-loaded microneedles (left images (Fig. 7a): conventional single-layer microneedles, right images (Fig. 7b): exemplary microneedles of the present invention). The dotted outline indicates location where the microneedles were inserted. Fig. 8 illustrates pharmacodynamics and pharmacokinetics of insulin delivered by the microneedle patch of Example 1 to diabetic rats. Fig. 8a shows the average blood glucose level of all rats in each group (n = 3). Fig. 8b shows the average serum insulin level of all rats in each group (n = 3).

DETAILED DESCRIPTION

The invention will now be described in detail in conjunction with the drawings in order to gain a better understanding. The same reference numbers as in the drawings are used and explain identical or similar elements or elements with the same function throughout the description of the invention.

Any aspects shown herein shall encompass the application to other aspects of the present invention as well, unless stated otherwise.

Technical terms and scientific terms used herein have meanings as understood by a person of ordinary skill in the art, unless specified otherwise.

Throughout the present invention, the term “about” is used to indicate that any values appearing or shown herein may be varied or deviate. Such variation or deviation may be caused by equipment error, or method used to determine the values.

The terms “consist(s) of,” “comprise(s),” “contain(s),” “have/has”, and “include(s)” are open-ended verbs. For example, any method which “consists of,” “comprises,” “contains” or “includes” one component or multiple components or one step or multiple steps is not limited to only one component or one step or multiple steps or multiple components, but also encompasses components or steps that are not specified. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

Tools, devices, methods, materials, or chemicals mentioned herein, unless specified otherwise, mean the tools, devices, methods, materials, or chemicals generally used or practiced by a person skilled in the art.

Fig. 1 shows an exemplary embodiment of the microneedle patch according to the present invention. The microneedle patch comprises: a base (1) which is a sheet material having liquid-permeable cavities; and multilayered microneedles (2) having a proximal end adjacent to the base (1) and a distal end opposite thereto, the multilayered microneedles (2) comprising: a substance containing layer (2.3), and a penetrating tip (2.4) disposed at the distal end of the multilayered microneedles (2).

Preferably, the penetrating tip (2.4) does not contain a substance and can withstand at least 0.03 N of compressive force/needle.

According to the present invention, the base (1) should preferably be a sheet material having cavities that allow permeation of liquid. Said material should be non-toxic, does not cause skin irritation upon contact, and does not release any biotoxin chemical or fiber upon contact with liquid. Examples of appropriate sheet material for using as the base (1) according to the present invention are woven patch, non-woven patch, polymer patch having liquid-permeable cavities, synthetic fabric patch, natural fabric patch, different kinds of paper patch such as those made of fibers that does not contain a biotoxin filler or binder, or a combination thereof which can be selected without limitation by those skilled in the art.

For example, the woven patch is a synthetic fabric patch or natural fabric patch, the nonwoven patch is a paper, and the polymer patch having liquid-permeable cavities is an open-cell- sponge patch or porous hydrophilic polymer patch.

The base (1) can have different thicknesses depending on the application or design of the microneedle patch in various embodiments of the invention. For example, the base (1) may have a thickness in a range from 5 to 10,000 microns, preferably from 100 to 5,000 microns, more preferably from 100 to 3,000 microns.

According to the present invention, the multilayered microneedles (2) can be made of any materials that are non-biotoxin and bio-absorbable and bio-compatible. Examples of appropriate material used to make the multilayered microneedles (2) are cross-linked or non-cross-linked, bio-absorbable and bio-compatible polymer, preferably hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, chitosan, polypeptides, silkworm sericin, collagen, biocompatible carbohydrates, bio-absorbable sugar, polylactic acid-co-glycolic acid of any ratios of lactic acid to glycolic acid, or a combination thereof. Examples of appropriate sugar are maltose, galactose, glucose, sucrose, fructose, xylose, xylitol, and a combination thereof which can be selected without limitation by those skilled in the art.

The multilayered microneedles (2) can be of any shape so that it is suitable for the application. Distance between each microneedle (2) and pattern of arrangement on the base can be as desired. Also, the number of multilayered microneedles (2) per patch can be altered as appropriate. The substance containing layer (2.3) contains the substance to be delivered. Each multilayered microneedle can comprise of one or more substance containing layers (2.3). In some embodiments, the substance containing layer (2.3) comprises a plurality of sub-layers, each of the sub-layers contain same or different substances or made from materials with same or different solubility. Consequently, the release rate of the substance in each layer can be controlled.

The substance in the substance containing layer (2.3) can by any substance capable of delivering desired effects to users upon application of the microneedle patch to their skin. For example, the substance can be selected from a group consisting of active pharmaceutical ingredients, allergens, supplements, cosmetic ingredients, natural extracts, and a combination thereof. Examples of the substance are drugs, vaccines, vaccine adjuvants, viable cells, cancer cells, stem cells, RNA, DNA, vitamins, Botulinum toxin A, melanocytes, peptides, or a combination thereof. In some embodiments, the substance containing layer (2.3) contains tattoo ink, resulting in a tattoo microneedle patch. Notably, the examples of the substance mentioned herein are only intended to facilitate understanding of the present invention and not intended to limit the present invention. In one exemplary embodiment, the substance containing layer (2.3) contains insulin in hyaluronic acid and sorbitol. In another exemplary embodiment, the substance containing layer (2.3) contains mRNA in lipid nanoparticles mixed with polyethylene glycol or hyaluronic acid or sugar or a combination thereof. In yet another exemplary embodiment, the substance containing layer (2.3) contains tattoo ink mixed with hyaluronic acid or sugar or a combination thereof.

According to the present invention, the penetrating tip (2.4) is disposed at the distal end of the multilayered microneedles (2). The penetrating tip (2.4) helps the multilayered microneedles (2) to penetrate the skin during the application and remain embedded in the skin thereafter. Thus, the problem of “bouncing back” or ejection of the multilayered microneedles (2) from the skin when the microneedles are short and/or hydrophobic can be overcome. As mentioned above, this is especially beneficial when the multilayered microneedles (2) are designed to deliver tattoo ink or cosmetic ingredients to upper skin layers, as short microneedles do not have sufficient retention in the skin and therefore are often ejected out. By having the penetrating tip (2.4) at the distal end, the length of the substance containing layer (2.3) and how deep it will be embedded in the skin can be individually adjusted without affecting the total length of the microneedles. In other words, the multilayered microneedles (2) can have sufficient length such that they are securely retained in the skin even when the substance containing layer (2.3) is designed to deliver a substance to the epidermis or even the stratum comeum. Another advantage is that materials that make up each layer can be chosen freely according to the desired properties without the concern that they will be too hydrophobic and cause the “bouncing back”.

One exemplary embodiment is a tattoo microneedle patch. By varying the length of the penetrating tip (2.4), it is possible to fabricate either a permanent, a semi-permanent, or a temporary tattoo.

A temporary tattoo sits on top of the skin and will last about a week before fading away. By concentrating the tattoo ink to the exact location without it diffusing to other areas using the tattoo microneedle patch according to the present invention, it is possible to make a temporary tattoo look even better by giving the instant impression that the artwork is under the skin like a permanent tattoo.

A Semi-permanent tattoo that supposedly lasts longer than a temporary tattoo should be delivered as deep as the epidermis and fades gradually over the weeks or months. There are several potential issues associated with this. One is that everybody’s skin is different. The thickness of the dermis and epidermis can vary. Also, skin at different parts of the body has different thickness. Therefore, when applying a semi -permanent tattoo using a conventional technique, some of the ink might end up in the dermis and become permanent. There have been instances where some of a tattoo has faded with time while part of the design is permanent. That person will have to live with a partial tattoo which is not aesthetically pleasing. Such problem can be prevented by using the tattoo microneedle patch according to the present invention, where the ink from each microneedle can be delivered to the same skin depth, creating a uniformly lasting tattoo. Or, if a person getting a tattoo would like some part of the design to fade overtime and some part to be permanent, it is also possible to achieve that by the present invention, as each microneedle on a patch can be individually designed, color-wise, structure-wise, and material-wise.

For a permanent tattoo, the ink will be delivered a couple of layers down inside the skin. It goes through the outer layer, the epidermis, and to the epidermis, where it permanently stays there.

By applying a microneedle patch according to the present invention as a tattoo patch, it is possible to create a customized design and choose either to have it as temporary, semipermanent, or permanent tattoo by varying the length and position of the ink containing layer, i.e., the substance containing layer (2.3). In the case that the substance containing layer (2.3) is only embedded in an outer skin layer or epidermis, for example, in case of temporary or semipermanent tattoo, one can increase the length of the penetrating tip (2.4) such that the total length of the microneedles is sufficient to prevent ejection from the skin. Fig. 2 shows exemplary embodiments of the tattoo microneedle patch according to the present invention. Fig. 2a illustrates a microneedle patch for temporary tattoo and Fig. 2b illustrates a microneedle patch for permanent tattoo. As can be seen from the figures, it is possible to fabricate the microneedles with the same total length while having the ink delivered to the desired skin depth.

Besides the tattoo, the feature of the penetrating tip (2.4) is also useful for delivering drugs or cosmetic ingredients to the upper skin layer. For example, a multivitamin patch having a vitamin C loaded layer targeted to epidermis for treating hyperpigmentation and a beta-glucan loaded layer targeted to stratum comeum for skin soothing and anti-inflammation.

For the penetrating tip (2.4) to effectively perform skin penetrating function, it must be able to withstand certain compressive force. In the present invention, the inventor has performed a mechanical strength testing using a universal testing machine (Shimadzu EZ-S, Japan). As shown in Fig 3., a sample was placed on an acrylic plate with microneedles facing upward. The acrylic plate was then put into a machine containing a compressing probe. The maximum compressive force was set to 250 N. The sample was compressed by the probe during the measurement, and a displaced distance was recorded along with the compressive force. Materials used for making the penetrating tip could withstand compressive force of at least 0.03 N/needle, preferably in a range of 0.03-80 N/needle, more preferably in a range of 0.05-30 N/needle. By comprising the penetrating tip with said property, the microneedle patch according to the present invention could withstand compressive force of 10-300 N/patch, preferably 20-150 N/patch. Notably, the mechanical strength required for the penetrating tip will depend on applications. For example, those to be used on rabbit skin will require different mechanical strength than those to be used on human skin. Different skin areas also have different properties.

In some embodiments, the multilayered microneedles (2) according to the present invention are formed to have variations of structure or material or substance or a combination thereof. As a result, an assorted patch, i.e., a patch where microneedles having different functions are on the same patch, can be achieved. One advantage is that substances that should not be mixed, for example, those that will precipitate or react when mixed, can be separated into different microneedles on the same patch. Also, it provides the ability to design patterns of substance to be delivered, for example, pigments, dyes, or tattoo inks.

One example of the assorted patch that has already been discussed above is a tattoo patch. With each multilayered microneedle (2) containing pigments/dyes/tattoo inks of different colors, or being empty (no color), a tattoo having desired pattern can be created. Fig. 4 illustrates how the tattoo patch according to the present invention can be used. Individual multilayered microneedle (2) is loaded with polymer mixed with different pigments (customized design) (left drawing), and then applied onto the skin (right drawing). Another example is an ache healing patch, where substance in each microneedle is either an acne healing agent, an anti-inflammatory agent, or a skin soothing agent, with either similar or different releasing time.

In some embodiments, the multilayered microneedles (2) according to the present invention further comprise a connecting layer (2.1) connecting a bottom portion of the multilayered microneedles (2) to the base (1). Specifically, the multilayered microneedles (2) are assembled to the base (1) through the connecting layer (2.1), where the connection between the multilayered microneedles (2) to the base (1) is formed through a penetrating structure in which part of the connecting layer (2.1) penetrates the base (1), occupy some or all cavities of the base (1). Upon wetting the base, using any convenient means such as placing a water pad on top, spraying with liquid or dripping liquid onto the base (1), said penetrating structure of the connecting layer (2.1) is dissolved, allowing the multilayered microneedles (2) to detach from the base (1). As a result, the base (1) can be removed without the multilayered microneedles (2) embedded in the skin being withdrawn. Hence, there are no visible microneedles left on the base or on the applied skin.

The connection through the connecting layer (2.1) of the present invention has a significantly advantageous effect on the detachment speed of the multilayered microneedles (2) from the base (1). In particular, it can overcome one of the major problems in the art of microneedles in that the microneedles cannot be detached from the base fast enough, consequently, the base must remain attached to the skin for a sufficiently long time and can be removed only after the microneedles embedded in the skin are substantially completely dissolved. Leaving the base which is still connected to the microneedles on the skin for a long time causes a negative effect, i.e. making the openings on the skin last longer, therefore posing a risk of infection and requiring skin repair afterward which will cause undesired dark spots on the user’s skin. In case where the base is removed before the microneedles are detached from the base, some of the microneedles will be withdrawn together with the base, therefore compromising the delivery efficiency. For this invention, as the penetrating structure where part of the connecting layer (2.1) penetrates the base (1) cavities can be quickly dissolved upon wetting the base (1), such problem can be overcome.

In some embodiments of the present invention, the connecting layer (2.1) is a single integrated piece connecting all multilayered microneedles (2) to the base (1). In further embodiments, the connecting layer (2.1) comprises a plurality of separated pieces, each piece connecting one or more multilayered microneedles (2) to the base (1). Fig. 5 shows some variations of individual and grouped connecting layer (2.1). Owing to these variations, specific connection for different microneedles with different substances on the same patch can be achieved. It also helps prevent mixing of substances between different needles and renders the patch more flexible. For a tattoo patch, individual or grouped connecting layer (2.1) will allow for higher resolution pattern.

In further embodiments, the substance containing layer (2.3) and the connecting layer (2.1) are made from the same material and are integrally formed. For example, for a temporary tattoo, part of the ink containing layer may also penetrate the base (1), connecting the bottom portion of the multilayered microneedles (2) to the base (1), hence, function as a connecting layer (2.1).

In some embodiments, the multilayered microneedles (2) according to the present invention further comprise a barrier layer (2.2). The barrier layer (2.2) according to the present invention has a barrier function and is disposed such that it prevents migration or diffusion of a substance in the substance-containing layer (2.3), or a component of a particular layer, to an undesired direction, as well as prevent undesired mixing between layers.

There can be one or more barrier layers (2.2) in each multilayered microneedle (2), and it can be arranged in any order depending on intended applications. In one exemplary embodiment, the barrier layer (2.2) is disposed between the substance containing layer (2.3) and the connecting layer (2.1) such that it prevents reverse flow of the substance to the skin surface. In another exemplary embodiment, the barrier layer (2.2) is disposed between the substance containing layer (2.3) and the penetrating tip (2.4). In yet another exemplary embodiment, one or more substance containing layer (2.3) is sandwiched between two barrier layers (2.2).

The barrier layer (2.2) of the present invention has advantageous technical effects that the migration of the substance in each layer can be individually controlled and the substance can be confined to a specific layer (if required). This will be particularly useful when the multilayered microneedles (2) have several layers. As a result, each substance is delivered to a desired skin layer, at a required rate, in an accurate amount.

The barrier layer (2.2) has a property that limits migration or diffusion of particular substances or components during fabrication and/or storage and/or use of the microneedle patch. The barrier layer (2.2) according to the present invention can be of a single or mixture of any biocompatible materials as long as the desired barrier effect can be achieved. In one exemplary embodiment, the barrier layer (2.2) has a solubility lower than that of the substance containing layer (2.3). In another exemplary embodiment, the barrier layer (2.2) has a viscosity higher than that of the substance containing layer (2.3). In yet another exemplary embodiment, the barrier layer (2.2) is made of a material that can dissolve in a solvent that substance in the adjacent layer cannot dissolve.

Examples of suitable material for the barrier layer (2.2) include all biocompatible polymers such as hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, chitosan, polypeptides, and any biocompatible carbohydrates. Polymer with high molecular weight is preferred as the high molecular weight will usually increase viscosity of the solution and slow down diffusion of components from adjacent layers. Nevertheless, low molecular weight can also be used if the fabrication process could be done quickly enough that the diffusion of components from adjacent layers is not significant. Various sugars such as sucrose, maltose, glucose, trehalose, sorbitol, xylitol, and fructose, for instance, can also be used.

The multilayered microneedles (2) of the present invention can be formed to have variations of structure or material or substance or a combination thereof. Layers of the multilayered microneedles (2) can be arranged in any order as appropriate, and the number of each layer is not limited.

The multilayered microneedles (2) according to the present invention allows delivery of different active ingredients to different skin layers or the same active ingredients at different rates. One example is a melatonin and multivitamin patch which comprises of four substance containing layers (2.3). Arranged from the distal end to the proximal end of the multilayered microneedles (2), those layers are (I) Melatonin loaded layer targeted for systemic absorption for well sleep, (II) Vitamin A loaded layer targeted for dermal rejuvenation during sleep, (III) Vitamin C and beta-glucan loaded layer targeted to epidermis for treating hyperpigmentation and for anti-inflammation, and (IV) Beta-glucan loaded layer targeted to stratum comeum for anti-inflammation. Another example is a long-acting insulin patch which comprises of four substance containing layers (2.3), all loaded with insulin. Arranged from the distal end to the proximal end of the multilayered microneedles (2), those layers are (I) for instant release of insulin, (II), for short release of insulin, (III) for slow release of insulin, and (IV) for very slow release of insulin. Using polymers with different dissolution rates or degradation rates at different layers allows the insulin to be released at different timings.

Fabrication Method

The microneedle patch according to the present invention can be fabricated using any techniques known in the art. Preferably, the microneedle patch according to the present invention is fabricated by the method invented by the inventors of the present invention.

For the purpose of aiding enablement, said preferred method for fabricating microneedles patch comprising steps of:

(a) providing a mold comprising one or a plurality of mold recess, the mold being disposed on a mold holder which is placed inside a housing;

(b) dispensing liquid material constituting microneedles into at least one of the mold recesses under a first pressure (Pl), the liquid material partially or completely filing the mold recesses;

(c) increasing a pressure inside the housing from the first pressure (Pl) to a second pressure (P2) so as to allow the liquid material to move downward toward the bottom of the mold recesses;

(d) drying the liquid material inside the mold recesses;

(e) repeating steps (b) to (d) until the mold recess are filled to a predetermined level;

(f) attached a base to the microneedles obtained from step (e), forming a microneedle patch; and

(g) drying the microneedles patch obtained from step (f) and removing it from the mold.

Notably, method of fabrication is not a limitation to the present invention.

Examples

Described below are some examples of the microneedle patch according to the present invention. Example 1: Insulin patch comprising layers 1-5, arranged in order from the tip of the microneedles to the base as below.

Layer 1 (penetrating tip)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 60 %

2) Hyaluronic acid, high-molecular weight, 2 MDa 5 - 50 %

3) Sorbitol 5 - 50 %

Layer 2 (insulin-containing layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 80 %

2) Hyaluronic acid, high-molecular weight, 2 MDa 5 - 30 %

3) Sorbitol 5 - 50 %

4) Insulin 5 - 20 %

Layer 3 (barrier layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 40 - 80 %

2) Hyaluronic acid, high-molecular weight, 2 MDa 5 - 50 %

3) Sorbitol 5 - 50 %

Layer 4 (connecting layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 40 - 90 %

2) Sorbitol 10 - 50 %

Layer 5 (base)

1) Polyester sheet

Example 2: mRNA patch comprising layers 1-5, arranged in order from the tip of the microneedles to the base as below.

Layer 1 (penetrating tip)

1) Hyaluronic acid, high-molecular weight, 0.1 MDa 20 - 80 %

2) Polyvinylpyrrolidone 90F 10 - 50 %

3) Sucrose 0 - 40 %

Layer 2 (mRNA -containing layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 80 % 2) Hyaluronic acid, high-molecular weight, 0.1 MDa 5 - 30 %

3) Sucrose 5 - 60 %

4) PEG 0.05 - 2 %

5) mRNA 0.001 - 1 %

Layer 3 (barrier layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 80 %

2) Hyaluronic acid, high-molecular weight, 0.1 MDa 5 - 30 %

3) Hyaluronic acid, high-molecular weight, 0.3 MDa 5 - 30 %

4) Sucrose 5 - 50 %

Layer 4 (connecting layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 90 %

2) Carbopol 0 - 20 %

3) Sorbitol 5 - 50 %

Layer 5 (base)

1) Polyester sheet

Example 3 Hyaluronic acid filler patch comprising layers 1-5, arranged in order from the tip of the microneedles to the base as below.

Layer 1 (penetrating tip)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 60 %

2) Hyaluronic acid, high-molecular weight, 2 MDa 5 - 50 %

3) Trehalose 0 - 50 %

Layer 2 (hyaluronic acid filler-containing layer)

1) Crosslinked hyarulonic acid (hyaluronic acid filler) 80 - 100 %

2) Bioactive compounds such as appropriate peptides and and/or vitamins and/or plant extracts 0 - 20 %

Layer 3 (barrier layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 20 - 60 %

2) Hyaluronic acid, high-molecular weight, 2 MDa 5 - 30 % 3) Bioactive compounds such as appropriate peptides and/or vitamins and/or plant extracts 0 - 20 %

4) Trehalose 5 - 50 %

Layer 4 (connecting layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 40 - 90 %

2) Sorbitol 10 - 50 %

Layer 5 (base)

1) Polyester sheet

Example 4 Tattoo microneedle patch comprising assorted microneedles on the same patch. Each needle has layers 1-4, arranged in order from the tip of the microneedles to the base as below.

Layer 1 (penetrating tip)

1) Hyaluronic acid 30 - 100 %

2) Sucrose 0 - 70 %

Layer 2 (ink-containing layer)

1) Hyaluronic acid 20 - 70 %

2) Ink (coloring agent) 10 - 60 %

3) Appropriate color stabilizing agent 5 - 30 %

4) Sucrose 20 - 60 %

Layer 3 (connecting layer)

1) Hyaluronic acid, low-molecular weight, 5 kDa 40 - 90 %

2) Carbopol 0 - 20 %

3) Sorbitol 5 - 50 %

Layer 4 (base)

1) Polyester sheet

Different needles have coloring agent in their layer 2, according to the pattern of the tattoo. Experiments

The insulin patch of Example 1 having layers and components in each layer as outlined above were tested in comparison with a conventional single-layer microneedle patch. The experiments and results are discussed below.

Physical appearance

Figs. 6a and 6b show the physical appearance of the multilayered microneedles of the insulin patch of Example 1. In particular, Fig. 6a shows a stereomicroscopic image and Fig. 6b shows a fluorescence image of the Eissamine Rhodamine B insulin-loaded multilayered microneedles. It can be seen that the microneedles have sharp tip indicating that no air bubble was trapped in the mold during fabrication. In addition, insulin is confined in the substance containing layer, indicating that the barrier layer successfully prevents diffusion of insulin out from the substance containing layer.

Skin penetrating ability

Fig. 7 shows a stereomicroscopic image of cross sectioned ex vivo porcine skin after an administration of Lissamine Rhodamine B - insulin-loaded microneedles (left images (Fig. 7a): conventional single-layer microneedles, right images (Fig. 7b): Example 1 of the present invention). In the left images, it can be seen that insulin was present along the entire skin depth and some reverse flow was observed. In the right images, on the other hand, insulin was delivered to the deeper layer as required and minimal to negligible amount of insulin was delivered to the upper skin layer. The reverse flow of insulin was also not observed. These results indicate that the multilayered microneedles of the present invention can effectively deliver the predetermined amount of the substance to the designated skin layer.

Pharmacodynamics and pharmacokinetics

Figs. 8a and 8b illustrate pharmacodynamics and pharmacokinetics of insulin delivered by the microneedle patch of Example 1 to diabetic rats. Fig. 8a shows average blood glucose level and Fig. 8b shows average serum insulin level of all rats in each group (n = 3) over 12 hours. It can be seen that the blood glucose level gradually decreases over time as insulin is gradually released from the microneedles into the blood stream. These results indicate that the microneedle patch according to the present invention can effectively deliver the substance of interest into the skin.

Claims

1. A microneedle patch comprising: a base (1) which is a sheet material having liquid-permeable cavities; and multilayered microneedles (2) having a proximal end adjacent to the base (1) and a distal end opposite thereto, the multilayered microneedles (2) comprising: a substance containing layer (2.3), and a penetrating tip (2.4) disposed at the distal end of the multilayered microneedles (2), wherein the penetrating tip (2.4) does not contain a substance and can withstand at least 0.03 N of compressive force/needle.

2. The microneedle patch according to claim 1, wherein the multilayered microneedles further comprise a connecting layer (2.1) connecting a bottom portion of the multilayered microneedles (2) to the base (1), a connection between the multilayered microneedles (2) to the base (1) being formed through a penetrating structure in which part of the connecting layer (2.1) penetrates the base (1), occupying some or all cavities of the base (1), the penetrating structure of the connecting layer (2.1) is dissolved upon wetting the base (1), allowing the base (1) to be removed from the skin while the multilayered microneedles (2) remain embedded in the skin.

3. The microneedle patch according to claim 2, wherein the substance containing layer (2.3) and the connecting layer (2.1) are made from the same material and are integrally formed.

4. The microneedle patch according to claim 1, wherein the multilayered microneedles (2) further comprise a barrier layer (2.2).

5. The microneedle patch according to claim 4, wherein the barrier layer (2.2) is disposed such that it prevents migration of the substance or components of the multilayered microneedles (2) to an undesired direction or undesired mixing between layers.

6. The microneedle patch according to claim 1, wherein the multilayered microneedles (2) are formed to have variations of structure or material or substance or a combination thereof.

7. The microneedle patch according to claim 2, wherein the connecting layer (2.1) is a single integrated piece connecting all multilayered microneedles (2) to the base (1).

8. The microneedle patch according to claim 2, wherein the connecting layer (2.1) comprises a plurality of separated pieces, each piece connecting one or more multilayered microneedles (2) to the base (1).

9. The microneedle patch according to claim 1, wherein the substance containing layer (2.3) comprises a plurality of sub-layers, each of the sub-layers containing same or different substance or made from material with same or different solubility.

10. The microneedle patch according to claim 1, wherein the base (1) is made of a material selected from woven patch, non-woven patch, polymer patch having liquid-permeable cavities, synthetic fabric patch, natural fabric patch, paper patch, or a combination thereof.

11. The microneedle patch according to claim 10, wherein the woven patch is a synthetic or natural fabric patch, the non-woven patch is a paper patch, and the polymer patch having liquid-permeable cavities is an open-cell-sponge patch or porous hydrophilic polymer patch.

12. The microneedle patch according to claim 1, wherein the multilayered microneedles (2) are made of a cross-linked or non-cross-linked, bio-absorbable and bio-compatible polymer material, selected from hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, chitosan, polypeptides, silkworm sericin, collagen, biocompatible carbohydrates, bio-absorbable sugar, or a combination thereof.

13. The microneedle patch according to claim 1, wherein the penetrating tip (2.4) can withstand 0.03-80 N of compressive force/needle.

14. The microneedle patch according to claim 1, wherein the microneedle patch can withstand 10-300 N of compressive force/patch.

15. The microneedle patch according to claim 1, wherein the microneedle patch can withstand 20-150 N of compressive force/patch.

16. The microneedle patch according to claim 1, wherein the substance containing layer (2.3) contains substance that is selected from a group consisting of active pharmaceutical ingredients, allergens, supplements, cosmetic ingredients, natural extracts, and a combination thereof.

17. The microneedle patch according to claim 1, wherein the substance containing layer (2.3) contains tattoo ink.