WO2025172984A1

WO2025172984A1 - Microneedle devices for delivery of agents into the skin

Info

Publication number: WO2025172984A1
Application number: PCT/IB2025/053596
Authority: WO
Inventors: Dewan Chowdhury
Original assignee: Individual
Current assignee: Individual
Priority date: 2024-02-16
Filing date: 2025-04-04
Publication date: 2025-08-21
Anticipated expiration: 2026-08-16
Also published as: GB2639767A; GB202411590D0; GB202505077D0

Abstract

Disclosed herein are various microneedle devices for the delivery of an active agent, into or onto skin, mucosa, tissue or the like, primarily using micro-projections. In one embodiment, a device comprises a primary substrate (9) including one or more primary micro-projections (1), for providing an active agent (4), and one or more secondary micro-projections (12), the or each respective pair of primary and secondary micro-projections being co-operable in use such that the secondary micro-projection of the pair acts on the primary micro-projection of the pair to urge the primary micro-projection of the pair into, or further into the skin.

Description

Microneedle devices for delivery of agents into the skin

This invention relates to microneedle devices for the delivery of active agents, such as therapeutic or cosmetic agents via skin, mucosa, tissue or the like.

Background

Microneedles represent a breakthrough in drug and vaccine delivery technology, offering a minimally invasive method to administer therapeutics through the skin. The history of microneedles traces back to the late 20th century, with early developments focusing on solid metal needles for transdermal drug delivery. Over time, researchers have explored various materials and designs to optimize microneedle performance.

Key materials used for microneedles include metals like stainless steel, polymers such as polyethylene glycol (PEG), biodegradable materials like polylactic acid (PLA), and dissolvable substances like sugar or silk. These materials are chosen for their mechanical strength, biocompatibility, and ability to carry and release drugs effectively. Microneedles are typically fabricated using microfabrication techniques such as micromolding, laser cutting, or photolithography.

The substrate, or base, on which microneedles are mounted plays a crucial role in their functionality. Common substrate materials include silicon, glass, and flexible polymers like polydimethylsiloxane (PDMS). The substrate provides structural support for the microneedles and can also be designed to incorporate reservoirs for drug storage or additional functionalities.

Microneedles are inserted into the skin using various methods depending on their design and application. Some microneedles are manually applied using a patch-like device, where the user presses the microneedle array against the skin with gentle pressure. Other microneedle systems utilize applicator devices, which can ensure consistent insertion depth and minimize user variability. Additionally, advancements in microneedle technology have led to the development of microneedle patches that can be applied and worn for a specified duration to facilitate drug delivery.

The insertion depth of microneedles typically ranges from tens to a few hundred micrometers to a few millimeters, depending on the target depth for drug delivery and the desired balance between efficacy and patient comfort. Microneedles create microchannels in the outermost layer of the skin, the stratum corneum, facilitating the penetration of drugs or vaccines into the underlying dermal layers. The duration of microneedle application on the skin varies depending on factors such as the formulation of the drug or vaccine, the desired release kinetics, and the specific requirements of the therapeutic application. In some cases, microneedle patches may need to remain on the skin for several hours or even days, to allow for adequate drug or vaccine delivery, while in other cases, rapid dissolution or release mechanisms may facilitate shorter application times of tens of minutes.

In summary, microneedles represent an innovative approach to drug and vaccine delivery, offering advantages such as improved patient compliance, reduced invasiveness, and enhanced therapeutic efficacy. Key materials used in microneedle fabrication include metals, polymers, and biodegradable substances, while substrates provide structural support and additional functionalities. Microneedles can be inserted into the skin manually or using applicator devices, with application times varying depending on the specific requirements of the therapeutic application.

Various types of microneedles have been developed and investigated in clinical trials for drug and vaccine delivery. These microneedles can be categorized based on their structure, material, and mechanism of action. Here are some of the key types:

Solid Microneedles:

Solid microneedles consist of sharp, solid needles typically made from materials like metals (e.g., stainless steel), polymers (e.g., polycarbonate, poly(methyl methacrylate)), or ceramics. They physically penetrate the stratum corneum to create microchannels, allowing drugs or vaccines to diffuse into the skin. Solid microneedles are relatively simple in design and have been used in various clinical trials for transdermal delivery of drugs and vaccines.

Coated Microneedles:

Coated microneedles feature a coating of drug formulation on the surface of the microneedles. These coatings can be designed to dissolve or release the drug upon insertion into the skin, facilitating controlled and localized drug delivery. Coated microneedles offer advantages such as precise dosing and enhanced stability of labile drugs or vaccines. They have been investigated in clinical trials for applications ranging from vaccination to the treatment of various medical conditions. Hollow Microneedles:

Hollow microneedles feature channels or lumens within the needles, allowing for the direct injection or infusion of drugs or vaccines into the skin. These microneedles can be connected to syringes or pumps to deliver precise volumes of therapeutics. Hollow microneedles offer advantages such as rapid drug delivery and the ability to administer a wide range of drug formulations, including viscous or particulate formulations. They have been studied in clinical trials for applications such as insulin delivery, vaccination, and local anaesthesia.

Dissolving Microneedles:

Dissolving microneedles are fabricated from biodegradable materials that dissolve or degrade upon insertion into the skin, releasing encapsulated drugs or vaccines. These microneedles eliminate the need for needle removal and reduce the risk of needlestick injuries and medical waste. Dissolving microneedles have been investigated in clinical trials for applications including vaccination, hormone delivery, and pain management.

Hydrogel-forming Microneedles:

Hydrogel-forming microneedles are composed of swellable polymers that form hydrogel matrices upon insertion into the skin. These microneedles can encapsulate drugs or vaccines within the hydrogel matrix, which gradually releases the therapeutic agent into the skin. Hydrogel-forming microneedles offer advantages such as sustained drug release and improved patient comfort. They have been evaluated in clinical trials for applications such as vaccination and drug delivery.

Overall, microneedle technology offers a versatile platform for the delivery of drugs and vaccines, with various types of microneedles being investigated in clinical trials. These microneedles hold promise for improving patient compliance, enhancing therapeutic efficacy, and reducing the risks associated with conventional needlebased delivery methods. Continued research and development in this field are expected to lead to the commercialization of microneedle-based products for a wide range of medical applications in the future. Microneedles offer several key advantages for drug and vaccine delivery compared to traditional needle-based methods or other transdermal delivery systems. Some of the key advantages include:

Minimally Invasive:

Microneedles create microscopic channels in the outermost layer of the skin (stratum corneum) without reaching nerve endings, resulting in minimal pain or discomfort for the patient. This minimally invasive approach reduces the fear and anxiety associated with needle-based injections, improving patient acceptance and compliance.

Enhanced Patient Compliance:

The painless and simple application of microneedles, particularly in the form of patches, can improve patient compliance, especially for individuals who are needlephobic or require frequent injections. Microneedle patches can be self-administered, reducing the need for healthcare professionals, and enabling convenient at-home or point-of-care delivery.

Improved Safety:

Microneedles significantly reduce the risk of needlestick injuries and transmission of bloodborne pathogens compared to traditional hypodermic needles. This makes microneedles safer for both patients and healthcare workers, particularly in settings where infection control is a concern.

Precise Drug Delivery:

Microneedles enable precise and targeted delivery of drugs or vaccines to specific skin layers or tissues, bypassing the need for systemic administration. This localized delivery can enhance therapeutic efficacy while minimizing systemic side effects and reducing the required dosage of the therapeutic agent.

Stability of Labile Molecules:

Microneedles can be engineered to encapsulate labile drugs or vaccines within protective matrices, preserving their stability and bioactivity during storage and delivery. This enables the delivery of a broader range of therapeutic agents, including proteins, peptides, nucleic acids, and vaccines, which may be susceptible to degradation under conventional injection methods.

Flexibility in Formulation and Administration:

Microneedles offer flexibility in the formulation and administration of drugs or vaccines, accommodating a wide range of drug properties, including molecular weight, solubility, and pharmacokinetics. Microneedles can be designed as solid, coated, hollow, dissolving, or hydrogel-forming structures, allowing for tailored release kinetics and application methods based on the specific therapeutic requirements.

Reduced Medical Waste:

Microneedles, particularly dissolving or biodegradable microneedles, eliminate the need for needle disposal and reduce medical waste generation compared to traditional needle-based delivery systems, since the formed needles dissolve and dissipate into the skin. This contributes to environmental sustainability and reduces the burden on healthcare facilities for waste management.

Overall, microneedles represent a promising and versatile platform for drug and vaccine delivery, offering advantages such as minimal invasiveness, enhanced patient compliance, improved safety, precise drug delivery, stability of labile molecules, formulation flexibility, and reduced medical waste. Continued research and development in microneedle technology are expected to lead to the commercialization of innovative products that address unmet medical needs and improve healthcare delivery worldwide.

While microneedles offer several advantages for drug and vaccine delivery, they also have some key disadvantages and limitations that need to be considered. These disadvantages include:

Limited Drug Payload:

Microneedles have a limited capacity to carry drugs or vaccines compared to conventional hypodermic needles. The small size of microneedles restricts the volume of therapeutic agents that can be delivered in a single application. This limitation may pose challenges for delivering high-dose medications or large vaccine doses, especially for treatments requiring frequent administration. Formulation Challenges:

Formulating drugs or vaccines for delivery via microneedles can be challenging. Some therapeutic agents may not be suitable for encapsulation within microneedle matrices or may require specialized formulations to achieve desired release kinetics. Formulation issues such as drug stability, solubility, and compatibility with microneedle materials need to be addressed to ensure efficacy and safety.

Skin Variability:

The effectiveness of microneedle-based delivery can vary depending on individual skin characteristics, such as thickness, hydration, and elasticity. Variability in skin properties among different patient populations, age groups, and anatomical sites may affect the reproducibility and consistency of drug or vaccine delivery using microneedles.

Complex Manufacturing Process:

Fabricating microneedles with precise dimensions and properties requires sophisticated microfabrication techniques, which can be costly and time-consuming. Scaling up production to meet commercial demand while maintaining quality and consistency presents additional challenges. Moreover, the integration of microneedles with drug formulations or delivery systems adds complexity to the manufacturing process.

Risk of Microneedle Breakage or Detachment:

Microneedles, especially solid or coated microneedles, may be prone to breakage or detachment during application, particularly if excessive force is applied or if the skin is not properly prepared. Broken or detached microneedles can cause discomfort, injury, or incomplete drug delivery, compromising treatment efficacy and patient safety.

Limited Depth of Penetration:

Depending on their design and application method, microneedles may have a limited depth of penetration into the skin, which can restrict their applicability for certain therapeutic applications. Achieving precise targeting of specific skin layers or tissues may require optimization of microneedle geometry and insertion parameters.

Regulatory Considerations:

The regulatory approval process for microneedle-based drug and vaccine delivery systems may pose challenges due to the unique characteristics of microneedle technology. Regulatory agencies require comprehensive safety and efficacy data, as well as demonstration of manufacturing consistency and quality control, before approving microneedle products for clinical use.

Overall, while microneedles offer promising advantages for drug and vaccine delivery, addressing these key disadvantages is essential to realize their full potential in clinical practice. Continued research and development efforts aimed at overcoming these challenges are needed to advance microneedle technology and facilitate its widespread adoption in healthcare.

The duration for which a patch needs to remain on the skin for the delivery of a vaccine or drug depends on several factors, including the formulation of the therapeutic agent, the design of the patch, and the desired pharmacokinetics of delivery. Here, we discuss these factors in detail:

Formulation of the Therapeutic Agent:

The formulation of the vaccine or drug plays a critical role in determining the release kinetics and absorption profile upon application to the skin. Some formulations are designed for rapid release and absorption, allowing for shorter application times, while others are formulated for sustained release, necessitating longer application durations to achieve therapeutic efficacy.

Rapid Release Formulations:

Formulations that rapidly dissolve or disperse upon contact with the skin can facilitate quick absorption of the therapeutic agent. These formulations may require relatively short application times, typically ranging from a few minutes to half an hour, depending on the specific characteristics of the formulation and the intended depth of penetration into the skin.

Sustained Release Formulations: Formulations designed for sustained release aim to prolong the delivery of the therapeutic agent over an extended period. These formulations may contain excipients or polymers that control the release rate of the drug, resulting in a gradual and sustained absorption profile. Longer application durations, ranging from several hours to overnight, may be necessary to achieve optimal drug levels in the bloodstream or target tissues.

Patch Design and Microneedle Properties:

The design of the patch, including the type and density of microneedles, can influence the rate and extent of drug delivery into the skin. Additionally, the properties of the microneedles, such as their length, composition, and geometry, can affect the depth of penetration and the rate of drug release.

Microneedle Length and Density:

Longer microneedles can penetrate deeper into the skin, reaching target layers or tissues for drug delivery. However, deeper penetration may require longer application times to ensure sufficient drug absorption. Higher microneedle densities can enhance drug delivery by increasing the surface area of contact with the skin, potentially reducing the required application duration.

Patch Adhesion and Occlusion:

Proper adhesion of the patch to the skin is essential to ensure uniform contact and effective delivery of the therapeutic agent. Occlusive patches that seal the application site can enhance drug absorption by maintaining a favourable environment for transdermal permeation. Longer application times may be needed for occlusive patches to allow for sufficient drug diffusion and absorption.

Target Site and Therapeutic Objective:

The target site of action and the therapeutic objective also influence the duration of patch application. For vaccines targeting immune cells in the skin or underlying lymphoid tissues, longer application times may be necessary to stimulate an optimal immune response. Similarly, for drugs targeting specific skin conditions or localized pain relief, longer application durations may be required to achieve therapeutic efficacy.

In summary, the duration for which a patch needs to remain on the skin for vaccine or drug delivery varies depending on the formulation of the therapeutic agent, the design of the patch, and the intended pharmacokinetics of delivery. Rapid-release formulations may require shorter application times, while sustained-release formulations or patches with specific microneedle properties may necessitate longer application durations to achieve therapeutic efficacy. Optimizing these factors is crucial to ensure effective and convenient delivery of vaccines and drugs via transdermal patches.

Problem to be solved

Long skin residence times for microneedle patches, while advantageous for some applications, can also pose significant disadvantages and challenges. Here are several reasons why prolonged skin residence times can be problematic:

Skin Irritation and Sensitivity:

Prolonged contact with microneedles can lead to skin irritation, inflammation, and discomfort. The mechanical disruption caused by microneedles and the presence of foreign materials on the skin surface may trigger local immune responses or allergic reactions, particularly in individuals with sensitive or reactive skin. Prolonged skin residence times increase the risk of adverse skin reactions, compromising patient comfort and compliance.

Risk of Infection:

Extended skin residence times increase the risk of microbial contamination and infection at the application site. Microneedles may create microinjuries or breaches in the skin barrier, providing entry points for pathogens and opportunistic organisms. Inadequate hygiene practices or environmental factors can further exacerbate the risk of infection, especially in settings with limited access to sanitation facilities or healthcare resources. Skin Damage and Trauma:

Prolonged mechanical stress on the skin from microneedle patches can cause tissue damage, trauma, or abrasions, particularly if the patches are applied to sensitive or fragile skin areas. Continuous pressure or friction exerted by the microneedles may lead to skin erosion, blisters, or ulceration, compromising the integrity of the skin barrier and increasing susceptibility to infections or secondary complications.

Impairment of Skin Barrier Function:

Prolonged exposure to microneedles can disrupt the natural barrier function of the skin, impairing its ability to regulate moisture, temperature, and microbial flora. Persistent microneedle-induced microinjuries or alterations in skin physiology may compromise the integrity of the stratum corneum, leading to increased transepidermal water loss, decreased skin hydration, and susceptibility to environmental irritants or allergens.

Inconvenience and Discomfort:

Long skin residence times impose practical limitations and inconvenience for patients, particularly in daily activities or during prolonged wear. Patients may experience discomfort, restriction of movement, or difficulty performing routine tasks due to the presence of microneedle patches on the skin. Moreover, prolonged wear of patches may interfere with personal hygiene practices, clothing choices, or social interactions, impacting quality of life and patient adherence to treatment regimens.

Risk of Adhesive Residue or Allergies:

Prolonged adhesive contact with the skin from microneedle patches may result in adhesive residue buildup or adhesive-related skin reactions, such as contact dermatitis or adhesive allergies. Adhesives used in patches can contain sensitizing agents or allergens that may cause skin irritation or hypersensitivity reactions upon prolonged exposure. Managing adhesive-related issues can be challenging and may require alternative patch designs or skin-friendly adhesive formulations.

In summary, while microneedle patches offer advantages for transdermal drug delivery, prolonged skin residence times can present significant disadvantages, including skin irritation, infection risk, tissue damage, impaired barrier function, inconvenience, and adhesive-related issues. Balancing the benefits and drawbacks of long skin residence times is essential to optimize the safety, efficacy, and patient acceptance of microneedle-based delivery systems.

Reducing skin residence time for microneedle patches can help mitigate potential drawbacks associated with prolonged wear, such as skin irritation, discomfort, and inconvenience. Several strategies can and have been employed to minimize skin residence time while maintaining effective drug delivery. Here are the key approaches that have been used by researchers:

Optimize Microneedle Design:

Designing microneedles with shorter lengths or lower densities can reduce the depth of penetration into the skin and minimize the duration required for drug delivery. Fine- tuning the geometry, shape, and spacing of microneedles can optimize their interaction with the skin and enhance drug delivery efficiency without necessitating prolonged wear.

Enhance Drug Release Kinetics:

Formulating drugs or vaccines with rapid-release characteristics can facilitate quick absorption and minimize the duration of microneedle patch application. Incorporating excipients or carriers that promote rapid dissolution or dispersion of the therapeutic agent upon contact with the skin can accelerate drug delivery kinetics and shorten skin residence time.

Utilize Dissolving or Biodegradable Microneedles:

Employing microneedles made from biodegradable or dissolving materials can eliminate the need for patch removal after drug delivery. These microneedles gradually dissolve or degrade in the skin, releasing the encapsulated drug or vaccine and minimizing skin residence time. Dissolving microneedle patches offer the added advantage of reducing medical waste and simplifying disposal.

Implement Rapid Delivery Systems:

Developing microneedle patches with rapid delivery mechanisms, such as mechanical or pneumatic actuation, can enhance drug penetration and minimize skin residence time. These systems enable precise and controlled delivery of the therapeutic agent within a shorter duration, making them suitable for applications requiring fast-acting effects or on-demand drug administration and are usually associated with hollow microneedles whereby a liquid load is delivered through the lumen of a needle.

Optimize Patch Adhesion and Occlusion:

Improving the adhesion properties of microneedle patches and enhancing their occlusive properties can enhance drug absorption and reduce the required duration of skin contact. Using skin-friendly adhesives or innovative patch designs that conform to the skin's contours can enhance patch adherence and minimize premature detachment, allowing for shorter wear times.

Employ Microneedle Arrays with Rapid Dissolution Capabilities:

Integrating microneedle arrays with dissolution-enhancing technologies, such as pH- responsive polymers or effervescent agents, can accelerate microneedle dissolution and drug release upon application to the skin. These rapid dissolution capabilities shorten skin residence time and facilitate efficient drug delivery without compromising therapeutic efficacy.

Implement Smart or Responsive Delivery Systems:

Developing smart or responsive microneedle delivery systems that respond to physiological cues or external stimuli can enable on-demand drug release and minimize unnecessary skin residence time. These systems can be programmed to release drugs in response to specific triggers, such as changes in pH, temperature, or enzymatic activity, optimizing drug delivery kinetics and minimizing potential side effects associated with prolonged wear.

In summary, minimizing skin residence time for microneedle patches requires a multifaceted approach involving optimization of microneedle design, drug release kinetics, patch adhesion, and delivery mechanisms. By employing these strategies, it is possible to enhance the safety, efficacy, and patient acceptance of microneedlebased drug delivery systems while minimizing the duration of skin contact.

Detailed Description of the Invention This invention describes devices and methods for the immediate or near-instant delivery of a drug, vaccine, therapeutic or cosmetic agent, through the skin or mucosa, internal or external to the body, using micro-projections or micro-needles. The invention overcomes the issues described earlier with respect to prolonged skin residence time of microneedles and provides a breakthrough in the current state of the art, enhancing the application of microneedles in the delivery of agents to the surface of the body through skin and mucosa, as well as to organs and tissue (during surgery or as part of a surgical procedure specifically for this drug delivery purpose), without the need for any residence time of a patch or the microneedle carrier.

Microneedles or micro-projections are constructed, molded or assembled on a substrate whereby the needles are inserted in the skin, enabled by the strong mechanical integrity of the substrate. Usually large applicators of varying levels of sophistication are used to force the needles into the skin due to the bed of nail effect that arises from trying to insert arrays of dozens and often many hundreds of microneedles over a small surface area of a square centimetres. This invention relies on the substrate allowing a second series of micro-projections (secondary microprojection patch/array), which may or may not be sharp tipped, to penetrate the substrate upon which the first set of microneedles has been formed or assembled or attached. As a consequence, the second set of microneedles is able to either shear/scrape off/detach the coating, either fully or partially from the microneedles, or in the case of where the needles are formed from a dissolvable formulation that can remain inside the skin or body, the second set of projections can act to press upon the apex of the first set of micro-projections detaching them from the substrate and leaving them in the skin, or detaching them from the substrate to which they are releasably located or attached and pushing them deeper into the skin to the desired depth. As a result the microneedles or the coating on the microneedles on the first substrate will instantly detach and remain in the skin allowing the first substrate or microneedle patch and the secondary micro-array projections to be immediately removed from the skin or tissue to which it has been applied, ensuring a controlled amount, or 100% of the dose of the agent being delivered, or the majority of the dose intended to be delivered to have been delivered without any residence time on the skin, mucosa, or internal tissue or organ.

The invention is defined by the claims and embodiments of the invention are described below with the aid of the drawings wherein:- Figure 1 shows a micro-projection is shown with an apex 1 , or distal region, and tip 2, or proximal region;

Figure 2 shows a micro-projection with an apex 1 , tip 2, and length 3 shown in this case with a curvature or concave region, though any shape that can be molded or casted can be formed.

Figure 3 shows a micro-projection shown with apex 1 , tip 2, and a layer 4 depicted herein via a cross section and shown to be across a partial length of the projection, although this layer may be a partial coating or temporary attachment to the microprojection, or completely surround the micro-projection including the tip region, or sit in a concave region or recess on the needle length 3 as shown in Figure 2, of the micro-projection. This layer is intended to depict the drug, vaccine, cosmetic or therapeutic agent, or (nano) particles or aggregates or complex that is to be delivered to the skin, mucosa, tissue or organ, hereinafter referred to as the payload containing the ‘active’ agent and excipients or carriers.

Figure 4 shows a single micro-projection shown with an attachment or payload layer 5, which is detachably linked to the length of the micro-projection.

Figure 5 shows a plan view of the apex 1 or distal regions of the micro-projections. 4 micro-projections are indicated in this schematic, though the number of microprojections could range from 1 to many dozens or hundreds.

Figure 5B shows a plan view of the apex 1 or distal regions of the micro-projections. 4 micro-projections are indicated in this schematic with vias 15 adjacent to the apex 1 of the micro-projections, through which another elongated micro-projection can pass. The vias in this case are depicted as being of a smaller diameter to the apex 1 of the payload microneedles, though it will be appreciated that the diameter and shape of the vias 15 can be optimised according to the shape and dimensions of the payload needles, such as triangular or sguare and it may be larger than the surface area of the apex 1 of the payload microneedles.

Figure 6 shows a plan view of the apex 1 regions of the micro-projections, with interlinks 6 to the apex regions of the apex of other micro-projections providing mechanical integrity and rigidity to the underlying payload microneedles. Figure 7 shows a schematic of a micro-projection shown with the apex 1 region which has a secondary apex structure 7 permanently or releasably attached to it protruding from the flat apex 1 region.

Figure 8 shows a plan view of micro-projections showing arms 8, connected to the apex 1 region of the micro-projections, in this case the arms are local to each payload microneedle and not interlinked.

Figure 9 shows a cross section schematic of a micro-projection showing the apex 1 , region, distal region 2, apex arms 8, and substrate 9 to which the micro-projections are anchored either releasably or permanently, i.e. , the microneedles are attached releasably or permanently to the substrate such that in the former case the entire (payload) microneedle may be detached and released into the skin.

Figure 10 shows a cross section schematic of a secondary micro-projection patch showing blunt micro-projections 11 , and substrate 10 to which the micro-projections are anchored.

Figure 11 shows a cross section schematic of a secondary micro-projection patch showing sharp-tipped micro-projections 11 , and substrate 10 to which the microprojections are anchored.

Figure 12 shows a cross section schematic of a secondary micro-projection patch showing angled-sharp-tipped micro-projections 13, and substrate 10 to which the micro-projections are anchored. The angle of the secondary micro-projections 13 may be pre-formed or formed in-situ during the process of inserting/applying the secondary micro-projection patches over the payload micro-projection patch, by forming these micro-projections from malleable/flexible materials without losing mechanical integrity. Figure 13 shows a cross section schematic showing micro-projection patch 1 with apex 1 region, payload layer 5, distal tip 2, apex arm 8 and substrate 9, and secondary micro-projection patch with substrate layer 10 and blunt projections 11.

Figure 14 is a cross sectional schematic depicting two micro-projection patches whereby the first, the secondary micro-projection patch is shown to have blunt projections 11 which have pierced or passed through a via on the substrate 9 of payload micro-projection patch 1 , and in doing so detached micro-projection patch 1 whereby the apex 1 region of the micro-projection is shown in proximity to the distal region of blunt projection 11 of a first micro-projection patch. A skin 14 region is shown to indicate the blunt projection follows through the substrate 9, and the skin 14 thus pushing the micro-projection into the deeper layer of the skin, or mucosa, or organ or tissue.

Figure 15 A is another cross sectional schematic depicting the secondary microprojection patch with substrate layer 10, and micro-projections 12, aligned with the payload micro-projection layer containing substrate layer 9, proximal end of microprojections 1 , distal end 2, and payload 4.

Figure 15 B is another cross sectional schematic as shown in Figure 15A showing the secondary micro-projection patch with sharp tipped projections 12 in a second activated position whereby they have pierced through or passed through vias on the payload patch substrate 9 and sheared off the payload (in this case shown as payload being only on one side of the needle) and thus instantly leaving the payload in the skin once the payload patch and secondary patches are immediately removed from the skin.

Figure 15 C is schematic of Payload 4 on distal tip of the payload micro-projections with distal 2 region and substrate 9, shown as shrouding the entire distal half of the micro-projection. This payload is releasably attached to the payload micro-projection such that a secondary micro-projection array may not be reguired to cause this payload to shear and remain in the skin. A pierceable layer 16 is shown as a restrain membrane to hold the payload 4 on the payload needle 2 during transit and storage. Whilst not shown here, the tip of the payload 4 may partially pierce the pierceable layer as part of the storage method to provide additional rigidity and security of the payload 4 from falling off the payload micro-projection distal tip 2.

Detailed description

Figure 1 is a schematic of a micro-projection. The term micro-projection and microneedle is used interchangeably here and describes a projection with a height greater than its width. The shape of the projection may be cylindrical, conical, star shaped, or any shape that has the ability to penetrate the skin, with suitable tip sharpness and exertion force.

Aspect Ratio: The aspect ratio refers to the ratio of microneedle length to width. A higher aspect ratio typically corresponds to longer and thinner microneedles. An ideal aspect ratio balances the need for sufficient penetration depth with mechanical stability and manufacturability. For most applications, microneedles with aspect ratios ranging from 2:1 to 6:1 are commonly used. However, in this case the aspect ratio whereby the height of the needle is greater than the diameter of the needle, is preferable.

Shape: Microneedles can have various shapes, including conical, pyramidal, cylindrical, or blade-like. Conical or pyramidal shapes are often preferred due to their ability to create precise microchannels in the skin with minimal trauma. Conical microneedles provide a gradual penetration profile, reducing the risk of skin damage or discomfort.

Size: Microneedle size is typically characterized by dimensions such as length, width, and base diameter. The size of microneedles depends on the target depth of penetration, skin thickness, and the volume of drug or vaccine to be delivered. Microneedles typically range in length from 10’s to 100’s of micrometres to a few millimetres, with widths in the range of 10 to 200 micrometres, though larger diameters of several hundred micrometres are used for longer micro-needles. Smaller microneedles may be suitable for shallow skin penetration or sensitive areas, while longer microneedles are required for deeper delivery or thicker skin.

Tip Sharpness: The sharpness of microneedle tips plays a crucial role in facilitating smooth penetration into the skin with minimal force. Sharp tips reduce the insertion force required and minimize tissue damage, resulting in a more comfortable and efficient delivery experience for the patient. Microneedles with tip radii ranging from a few nanometres to a few micrometres are typically preferred for skin delivery applications. However, excessively sharp tips may increase the risk of microneedle breakage or deformation during fabrication or application and tip sharpness of up to 10’s of micrometres have been successfully used.

The materials of construction may include any of the following:

Silicon: Silicon microneedles are often fabricated using semiconductor manufacturing techniques such as photolithography and etching. Silicon microneedles offer excellent mechanical strength, precise dimensions, and compatibility with microfabrication processes.

Stainless Steel: Stainless steel microneedles are robust and durable, making them suitable for clinical applications requiring repeated use. They can be fabricated using methods such as micromachining, laser cutting, or electrochemical etching. Stainless steel microneedles provide sharp tips and can penetrate the skin effectively for drug delivery. Polymers (e.g., Polydimethylsiloxane - PDMS): Polymers like PDMS offer flexibility, biocompatibility, and ease of fabrication, making them suitable for microneedle production. PDMS microneedles can be molded or cast using soft lithography techniques, enabling the creation of customized microneedle arrays with varying shapes and sizes.

Polycarbonate: Polycarbonate microneedles are transparent, rigid, and chemically resistant, making them suitable for visualization during insertion and drug delivery. They can be fabricated using techniques such as injection molding or hot embossing, offering scalability for mass production.

Biodegradable Polymers (e.g., Polylactic Acid - PLA): Biodegradable polymers like PLA degrade in the body over time, eliminating the need for microneedle removal after drug delivery. PLA microneedles can be fabricated using techniques such as micromolding or solvent casting, providing controlled release of encapsulated drugs or vaccines.

Hydrogels (e.g., Polyvinyl Alcohol - PVA): Hydrogel-forming materials swell upon hydration, enabling sustained release of drugs or vaccines from microneedle matrices. Hydrogel microneedles can be fabricated using methods such as photopolymerization or crosslinking, offering tunable drug release kinetics and improved patient comfort.

Silk: Silk proteins possess excellent mechanical properties, biocompatibility, and biodegradability, making them suitable for microneedle fabrication. Silk microneedles can be produced using techniques such as microfluidics or micromolding, offering controlled drug delivery and minimal tissue damage.

Glass: Glass microneedles are transparent and chemically inert, facilitating visualization during insertion and drug delivery. They can be fabricated using techniques such as micropipette pulling or laser ablation, offering precise control over microneedle geometry and dimensions.

Sugar (e.g., Dextran or Sucrose): Sugar-based materials can be used to fabricate dissolving microneedles that dissolve upon insertion into the skin, releasing encapsulated drugs or vaccines. Sugar microneedles can be fabricated using methods such as casting or molding, offering rapid drug delivery and minimal residual waste.

Ceramics (e.g., Titanium or Aluminum Oxide): Ceramic materials offer high mechanical strength, chemical stability, and biocompatibility, making them suitable for microneedle fabrication. Ceramic microneedles In the case where the needles are intended to detach from the substrate they may be produced from any number of materials widely cited in literature due to their mechanical properties in the dry form, and their bio-resorbable nature, including the following and analogues thereof, though not limited to these:

Polysaccharides (e.g., Hyaluronic Acid):

Natural polysaccharides like hyaluronic acid can be used to fabricate dissolving microneedles due to their biocompatibility, water solubility, and ability to form hydrogels, which aid in microneedle insertion and drug delivery.

Gelatin: Gelatin is a biodegradable protein derived from collagen and is commonly used to fabricate dissolving microneedles. It offers mechanical strength, flexibility, and biocompatibility, making it suitable for drug delivery applications.

Sodium Alginate: Sodium alginate is a natural polysaccharide extracted from brown seaweed. It forms hydrogels in the presence of calcium ions, providing mechanical support for microneedles while enabling controlled drug release and eventual biodegradation.

Polyvinyl Alcohol (PVA): PVA is a water-soluble synthetic polymer that can be used to fabricate dissolving microneedles. It offers mechanical stability, biocompatibility, and rapid dissolution properties, making it suitable for various drug delivery applications.

Polylactic Acid (PLA): PLA is a biodegradable polymer commonly used in drug delivery systems. It can be formulated into dissolving microneedles that provide mechanical support during insertion and drug delivery, with subsequent biodegradation and absorption by the body.

Polyglycolic Acid (PGA): PGA is another biodegradable polymer often used in conjunction with PLA to fabricate dissolving microneedles. It offers mechanical strength and biocompatibility and undergoes hydrolysis in the body to produce biocompatible byproducts.

Poly(lactic-co-glycolic acid) (PLGA): PLGA is a copolymer of PLA and PGA and is widely used in drug delivery systems due to its tunable degradation rate and biocompatibility. It can be formulated into dissolving microneedles to provide controlled drug release and biodegradation.

Polyvinylpyrrolidone (PVP): PVP is a water-soluble polymer known for its film-forming properties. It can be used to fabricate dissolving microneedles that offer mechanical support during insertion, controlled drug release, and eventual dissolution in the skin. Polyvinylpyrrolidone-vinyl acetate (PVP-VA): PVP-VA copolymers combine the water solubility of PVP with the film-forming properties of vinyl acetate. They can be used to fabricate dissolving microneedles with enhanced mechanical strength and drug delivery capabilities.

Sodium Hyaluronate (Hyaluronic Acid): Hyaluronic acid is a naturally occurring polysaccharide with excellent biocompatibility and moisture-retaining properties. It can be formulated into dissolving microneedles to provide mechanical support, hydration, and controlled drug release.

Polyethylene Glycol (PEG): PEG is a versatile polymer widely used in pharmaceutical formulations due to its biocompatibility and water solubility. It can be incorporated into dissolving microneedles to enhance mechanical properties, drug solubility, and biodegradability.

Carboxymethylcellulose (CMC): CMC is a water-soluble cellulose derivative with mucoadhesive properties. It can be used to fabricate dissolving microneedles that adhere to the skin surface, release drugs in a controlled manner, and eventually biodegrade within the body.

Figure 2 depicts a micro-projection with a concave region. This design of microneedle is intended to depict a region that either acts like a pocket or cavity or is able to provide a larger surface area such that the payload for the microneedle can releasably adhere with sufficient integrity that it does not detach until after it has been inserted into the skin. Henceforth ‘payload’ is defined as any material that is delivered using this microneedle based system, including but not limited to vitamins and minerals, drugs, therapeutics, biologies, vaccines and cosmetic agents. Furthermore henceforth skin is defined as superficial skin, mucosal surface including the inner lining of the mouth/gums, eyes/cornea, internal organ or tissue as may be accessed during surgery. Additional benefits of having a concave region on the microneedle include: Enhanced Drug Loading Capacity:

The concave region of the microneedle provides additional space for drug loading compared to flat or convex microneedles. This increased volume allows for higher drug payloads, enabling the delivery of larger doses or multiple drugs simultaneously.

Improved Drug Stability: The enclosed space within the concave region can protect sensitive drugs or biologies from degradation due to environmental factors such as light, oxygen, or moisture. This can enhance the stability and shelf-life of the encapsulated drugs, preserving their efficacy during storage and delivery.

Controlled Release Kinetics:

The shape and geometry of the concave microneedle can influence the release kinetics of the encapsulated drug. By modulating factors such as the depth of the concave region and the thickness of the microneedle walls, researchers can tailor the release profile to achieve sustained, controlled, or pulsatile drug delivery as desired. Increased Surface Area:

The concave shape of the microneedle surface can provide a larger surface area for drug interaction with the skin. This can enhance drug permeation and absorption through the microchannels created by the microneedles, potentially improving the bioavailability and therapeutic efficacy of the delivered drug.

Reduced Insertion Force:

In some cases, the concave shape of the microneedles may reduce the insertion force required for skin penetration compared to sharp-tipped microneedles. This can enhance patient comfort and reduce the risk of tissue damage or irritation during microneedle application.

Improved Microneedle Adhesion: The concave region of the microneedle can facilitate better adhesion to the skin surface compared to flat microneedles. This improved contact ensures uniform delivery of the encapsulated drug and minimizes the risk of microneedle detachment during application.

Figure 3 is a schematic of a micro-projection shown with apex 1 , tip 2, and a layer 4 depicted herein via a cross section and shown to be across a partial length of the projection, although this layer may be a partial coating or temporary attachment to the micro-projection, or completely surround the micro-projection, or sit in a concave region as shown in Figure 2, of the micro-projection from the proximal region toward the distal region or entirely shrouding the distal region (not shown in the schematic). This layer is intended to depict the payload that is to be delivered to the skin.

Materials that may be used for the coating may be produced from the following, and analogues thereof, though the list is not exhaustive: Polyvinyl Alcohol (PVA): PVA is a water-soluble polymer often used as a coating material for microneedles. It provides mechanical strength, flexibility, and biocompatibility while enabling controlled drug release and dissolution of the microneedles upon insertion into the skin.

Polyethylene Glycol (PEG): PEG is a versatile polymer widely used in pharmaceutical formulations due to its solubilizing, stabilizing, and lubricating properties. When coated onto microneedles, PEG can improve drug solubility, enhance skin penetration, and reduce friction during insertion.

Cellulose Derivatives (e.g., Hydroxypropyl Methylcellulose - HPMC): Cellulose derivatives such as HPMC are commonly used as film-forming excipients for coating microneedles. They provide a protective barrier, regulate drug release, and enhance adhesion to the skin surface.

Polyvinylpyrrolidone (PVP): PVP is a hydrophilic polymer known for its adhesive and film-forming properties. When coated onto microneedles, PVP improves drug solubility, enhances skin adhesion, and facilitates controlled drug release upon insertion.

Gelatin: Gelatin is a natural polymer derived from collagen and is commonly used as a coating material for microneedles. It provides mechanical strength, flexibility, and biocompatibility while enabling controlled drug release and dissolution of the microneedles.

Polylactic Acid (PLA): PLA is a biodegradable polymer widely used in drug delivery systems. When coated onto microneedles, PLA can serve as a protective barrier, control drug release kinetics, and facilitate microneedle fabrication using techniques such as dip coating or spray coating.

Polycaprolactone (PCL): PCL is another biodegradable polymer commonly used as a coating material for microneedles. It offers mechanical stability, biocompatibility, and controlled drug release properties, making it suitable for sustained drug delivery applications.

Chitosan: Chitosan is a biocompatible and mucoadhesive polymer derived from chitin. When coated onto microneedles, chitosan enhances adhesion to the skin, promotes drug penetration, and facilitates controlled drug release through its swelling and mucoadhesive properties.

Polyethyleneimine (PEI): PEI is a cationic polymer known for its mucoadhesive and permeation-enhancing properties. When coated onto microneedles, PEI can improve drug penetration through the skin and enhance the adhesion of microneedles to the skin surface.

Hydroxypropyl Cellulose (HPC): HPC is a cellulose derivative commonly used as a film-forming agent and viscosity enhancer in pharmaceutical formulations. When coated onto microneedles, HPC provides mechanical strength, flexibility, and controlled drug release properties.

Sodium Alginate: Sodium alginate is a natural polysaccharide extracted from brown seaweed. When coated onto microneedles, sodium alginate forms a hydrogel layer that improves adhesion to the skin, facilitates controlled drug release, and enhances patient comfort.

Sodium Hyaluronate (Hyaluronic Acid): Hyaluronic acid is a naturally occurring polysaccharide with excellent biocompatibility and moisturizing properties. When coated onto microneedles, hyaluronic acid enhances skin hydration, promotes drug penetration, and improves patient comfort during microneedle application.

Polyethylene Oxide (PEO): PEO is a water-soluble polymer known for its lubricating and film-forming properties. When coated onto microneedles, PEO reduces friction during insertion, improves drug solubility, and facilitates controlled drug release.

Acrylic Polymers (e.g., Eudragit®): Acrylic polymers such as Eudragit® are commonly used as coating materials for pharmaceutical dosage forms. When coated onto microneedles, acrylic polymers provide mechanical stability, controlled drug release properties, and protection of the encapsulated drug from environmental degradation.

Figure 4 is a schematic of a single micro-projection shown with an attachment or payload layer 5, which is detachably linked to the length of the micro-projection. The term detachable refers to a system whereby the payload is mechanically adhered or chemically bonded using mechanisms including but not limited to:

Physical Adsorption:

Drug molecules can adhere to the surface of microneedles through physical adsorption forces such as van der Waals interactions, hydrogen bonding, and electrostatic interactions. This mechanism relies on the affinity between the drug molecules and the surface of the microneedles, allowing for temporary attachment. Electrostatic Interactions: Charged drug molecules can interact with oppositely charged functional groups on the surface of microneedles through electrostatic interactions. By modifying the surface charge of microneedles or the drug formulation, electrostatic attraction can be utilized to adhere the active agent or payload to the microneedle surface.

Coating Layers:

Drug formulations can be coated onto the surface of microneedles using various coating techniques such as dip coating, spray coating, or layer-by-layer deposition. These coating layers provide a physical barrier that adheres to the microneedle surface and encapsulates the drug for controlled release upon insertion into the skin. Hydrogel Matrices:

Hydrogel-based drug formulations can be applied to microneedles to form a hydrated gel layer that adheres to the microneedle surface. Hydrogel matrices provide mechanical support, enhance drug stability, and enable controlled release of the drug upon hydration and dissolution in the skin.

Chemical Crosslinking:

Drug molecules can be chemically crosslinked or conjugated to functional groups on the surface of microneedles to form covalent bonds. Chemical crosslinking enhances the stability and durability of the drug-microneedle interface, preventing premature drug release or detachment during application. Note the term drug is used throughout, interchangeably with active agent to denote any drug, therapeutic agent, cosmetic agent, mineral or vitamin, vaccine or active or inactive inert particle to be delivered as a payload to or through the skin.

Encapsulation in Polymeric Carriers:

Drug molecules can be encapsulated within polymeric carriers or nanoparticles, which are then coated onto the surface of microneedles. These polymeric carriers protect the drug from degradation, control drug release kinetics, and adhere to the microneedle surface through physical or chemical interactions.

Hydrophobic Interactions:

Hydrophobic drug molecules or lipophilic excipients can interact with hydrophobic regions on the surface of microneedles through hydrophobic interactions. This mechanism enables the adhesion of lipophilic drugs or formulations to the microneedle surface, facilitating controlled release upon insertion into the skin. A key objective of this invention is to instantly deliver a payload into the skin using this microneedle device. The entire payload consisting of 100% of the payload material may be delivered or less than 100% may be delivered where the payload is semipermanently adhered to the microneedle and is mechanically sheared off the needle as depicted further below, for example.

Figure 5 is a plan view of the apex 1 or distal regions of the micro-projections. 4 microprojections are indicated in this schematic. In a given microneedle patch device anywhere from a minimum of 1 microneedle to over 1000 microneedles may be present. The pitch, needle height and width are preferably as follows:

Pitch: The pitch refers to the distance between individual microneedles within an array. Optimal pitch can vary depending on factors such as skin thickness, elasticity, and the desired coverage area. Generally, smaller pitches allow for denser arrays, which may improve drug delivery efficiency and skin coverage. However, excessively small pitches may increase the risk of tissue damage or discomfort and require vast forces to apply due to the bed of nail effect. The pitch of micro-projections for this device is greater than 50 micrometres where there is more than one micro-projection and more preferably greater than 100 micrometres where there is more than 2 micro-projections. Microneedle Height: The height of microneedles determines the depth of penetration into the skin. The optimal microneedle height depends on the target skin layer for drug delivery, with depths typically ranging from superficial (e.g., within the stratum corneum) to deeper layers (e.g., dermis). For the purposes of this invention the preferred needle height is greater than 50 micrometres though more preferably greater than 300 micrometers.

Microneedle Width: The width of microneedles influences their mechanical strength, flexibility, and ability to create microchannels in the skin. Thinner microneedles may offer improved patient comfort during insertion but may be more susceptible to breakage or bending. Conversely, wider microneedles may provide greater mechanical stability but may cause more tissue trauma. Microneedle widths typically range from tens to hundreds of micrometers, depending on the specific application and material properties. Importantly the microneedle may not be concentric and may have one side with a flat plane and another side that is conical for example, to both facilitate skin piercing as well as loading of the payload. Figure 5B. is a schematic indicating vias 15 adjacent to the apex 1 of the microneedles. Note that the substrate on which the microneedles are anchored is not shown here though it will be obvious to those skilled in the art that the needles must be anchored to a substrate of some form. The purpose of these vias as is evident from subsequent schematics is to allow a secondary projection to be forced through the substrate so as to mechanically shear the coati ng/payload from the microneedles that have been coated or to which a payload has been permanently, semi-permanently or releasably attached. This is a core part of the invention and builds on the current state of the art which consists of planar solid substrate to which the microneedles are anchored, since the primary mode of delivering a payload from a microneedle patch has been to press all the needles into the skin and allow the payload to dissolve off the needle or for the entire needle to dissolve and be absorbed into the skin and interstitial fluids.

Conventionally the substrate, or backing layer, provides structural support and stability to microneedles in a patch-based drug delivery system. Various materials can be used as substrates depending on factors such as flexibility, biocompatibility, and manufacturing requirements. Materials that may be used for the substrate layer include but are not limited to:

Polyethylene Terephthalate (PET):

PET is a thermoplastic polymer known for its strength, flexibility, and transparency. It is commonly used as a substrate for microneedle patches due to its mechanical properties and ease of fabrication.

Polyethylene (PE):

PE is a versatile polymer known for its chemical resistance, low cost, and ease of processing. It can be used as a substrate for microneedle patches, providing flexibility and durability.

Polypropylene (PP):

PP is a lightweight thermoplastic polymer with excellent chemical resistance and mechanical properties. It can be utilized as a substrate for microneedle patches, offering good dimensional stability and ease of processing.

Polyvinyl Chloride (PVC):

PVC is a widely used thermoplastic polymer known for its versatility and costeffectiveness. It can serve as a substrate for microneedle patches, providing flexibility and compatibility with various manufacturing processes. Polyurethane (Pll):

Pll is a flexible polymer with excellent abrasion resistance and mechanical properties. It can be employed as a substrate for microneedle patches, offering durability and comfort during application.

Polydimethylsiloxane (PDMS):

PDMS is a silicone-based elastomer known for its biocompatibility and flexibility. It can be used as a substrate for microneedle patches, providing softness and conformability to the skin.

Polymethyl Methacrylate (PMMA):

PMMA is a transparent thermoplastic polymer with excellent optical clarity and mechanical properties. It can serve as a substrate for microneedle patches, offering rigidity and dimensional stability.

Silicone Elastomers:

Silicone elastomers, such as medical-grade silicones, are highly biocompatible materials with excellent mechanical properties. They can be utilized as substrates for microneedle patches, providing softness, flexibility, and skin conformity.

Polyimide (PI):

PI is a high-temperature-resistant polymer known for its thermal stability and mechanical strength. It can be used as a substrate for microneedle patches, offering durability and resistance to harsh environmental conditions.

Polyester Fabric:

Polyester fabric, such as nylon or polyester mesh, can be used as a substrate for microneedle patches. The fabric provides flexibility, breathability, and adherence to the skin.

Biodegradable Polymers:

Biodegradable polymers, such as polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA), can serve as substrates for environmentally friendly microneedle patches. These polymers gradually degrade in the body, eliminating the need for patch removal after use.

Hydrogels:

Hydrogels are water-swollen polymer networks that provide hydration and mechanical support. They can be used as substrates for hydrogel-forming microneedle patches, offering softness, biocompatibility, and controlled release properties. 1 In this case the substrate and needle may be formed from the same material, and this is commonly the case.

Figure 6 is a plan view of the apex 1 regions of the micro-projections, with an interlink 6 to the apex regions of the apex of other micro-projections. This is a unique feature of this invention. One of the mechanisms described for instant delivery of a payload is to mechanically shear or detach, or move the payload to a position that is not in physical, chemical, mechanical or electrostatic interaction with the payload microprojection, whereby the payload on the micro-projection is partially or semipermanently adhered/anchored to the microneedle surface, by pushing a secondary micro-projection through a via(s) in the substrate or backing layer of the microneedle patch containing the payload. However, in another embodiment of this invention vias are not required, and in this case the secondary micro-projections pierce through the backing layer substrate of the first payload microneedle patch containing the payload and subsequently travel along or in proximity to the length of the microneedle containing the payload and mechanically shear or move the payload off or away from the microneedle thus instantly releasing it into the skin. In this case it may be that the microneedle and the substrate cannot be formed from the same material since it is a requirement that the microneedle containing the payload has sufficient mechanical strength to be able to pierce the skin, whereas the backing layer or substrate to which the microneedle is anchored must allow for either a blunt or sharp tipped microprojection to pierce through the material. A softer polymer that has greater elastic properties may therefore be used, including Polyurethane, silicone, Polyvinyl acetate and similar materials listed earlier. It is also conceivable that the substrate may not be a continuous layer and instead it formed of a mesh-like network, sufficient to anchor the microneedles containing the payload but having sufficient gaps between to allow the secondary projections to seamless pass through. The interlink 6 between microneedles is intended to describe and depict a mechanical connection between the proximal end or apex region of each microneedle which may or may not be formed from the same material as the microneedles. These interlinks may then remain suspended as a porous backing layer, or they may be immersed within a flexible pierceable material including any one of the materials previously listed, or a layer may be adhered to the interlink backing to provide a degree of mechanical rigidity yet allow the material to be pierced by a secondary projection. Figures 7 and 8 show an apex structure 7, and arms 8, both intended to act in a similar manner to the interlinks 6, except in this case they do not physically connect to the apex or proximal ends/base of the microneedles and instead they provide an increased surface area for either immersing into another flexible pierceable layer or a layer that is adhered to form the substrate to the which the microneedles are anchored.

Figure 9 is a cross section schematic of a micro-projection showing the apex 1 , region, distal region 2, apex arms 8, and substrate 9 on which the micro-projections are anchored either releasably or permanently. Note that whilst the arms 8 have been shown in this schematic, the needles may not have these arms 8, and may instead be anchored directly to the backing layer or substrate. This is specifically the case in a further embodiment of the invention where the payload is the entire microneedle structure. In this case the objective of the secondary projections will be to release the entire microneedle/payload into the skin by mechanically detaching it or moving it away from the backing layer substrate.

Figure 10 is a cross section schematic of a second micro-projection patch I the secondary projections showing blunt micro-projections 11 , and substrate 10 to which the micro-projections are anchored. The substrate in this case is intended to be relatively firm and able to enable the secondary micro-projections to either pierce through the substrate layer of the micro-projection backing layer/substrate of the payload patch, or to push the entire microneedle/payload of the payload patch such that it shears off the substrate.

Figure 11 is a cross section schematic of a second micro-projection patch showing sharp-tipped micro-projections 11 , and substrate 10 to which the micro-projections are anchored.

Figure 12 is a cross section schematic of a second micro-projection patch showing angled-sharp-tipped micro-projections 11 , and substrate 10 to which the microprojections are anchored. The purpose of the angled projections is to cater for conical- like shaped microneedles that may be present on the payload microneedle patch such that it mechanically shears the payload off the microneedles rather than going vertically into the skin and missing the payload altogether.

Figure 13 is a cross section schematic showing the payload micro-projection patch with apex 1 region, payload layer 5, distal tip 2, apex arm 8 and substrate 9, and microprojection patch 2 with substrate layer 10 and blunt projections 11. The schematic is intended to depict the proximity of the secondary projections to the payload microprojections when they pass through the vias, although in this case for the purposes of visual clarity the secondary projections 11 are shown adjacent to the payload 5.

Figure 14 is a cross section schematic depicting the two micro-projection patches whereby the secondary micro-projection patch is shown to have blunt projections 11 which have pierced or passed through a via or mesh on the substrate 9 of payload containing micro-projection patch 1 , and in doing so detached micro-projection patch 1 whereby the apex 1 region of the micro-projection is shown in proximity to the distal region of blunt (secondary) micro-projection 11 of the secondary micro-projection patch. A skin 14 region is shown to indicate the blunt projection follows through the substrate 9, and the skin 14 thus pushing the micro-projection into the deeper layer of the skin, or mucosa, or organ or tissue. In this case the entire microneedle or the majority portion of it may be composed of the payload. This is releasably anchored or adhered to the substrate layer 9, using one or more of the methods described earlier with respect to adhering the payload to the needles and substrates. An example being that the apex region 1 or 7 (as shown in figure 7) of the payload microneedles may be immersed in a soft polymer such that when the secondary micro-projections impact it, they remove away and become detached from the substrate 9 and can be pushed deeper into the skin. Note in this case the secondary micro-projection patch and payload micro-projection patch may both be superimposed and applied to the skin in a single insertion motion instead of having to press the payload micro-projections into the skin first followed by the secondary micro-projections, since the secondary microprojections will act to provide the mechanical support that the payload microprojections will need to facilitate their insertion into the skin. A key advantage of this embodiment of the invention is that almost 100% of the payload can be consistently delivered. A second advantage of this method, where the secondary projection 11 pierces through the substrate layer 9, is that there is no requirement for a via which would be highly complicated to produce and more complicated to align the secondary projections with the vias and this therefore constitutes a key inventive step overcoming a significant technical challenge. Two major additional advantages of this device configuration and method of payload delivery are that larger amounts of payload can be delivered per needle since the entire needle is composed of the payload, and secondly the depth of delivery can be precisely controlled by controlling the length of the secondary projections without having to make the payload microneedles themselves of significant lengths. This serves to resolve two additional technical challenges, firstly longer microneedles are more prone to fracture as discussed earlier, and secondly even where a microneedle could fracture and remain in the skin it would remain in the superficial layers of the skin with parts that may protrude from the skin surface, which would lead to serious potential for skin infection since the proximal end/base of the needles would remain very close to the surface of the skin and opening a conduit for the passage of microbes into the skin, and also potentially compromising the quantity of payload delivered as a portion will backflow or exude back out of the skin. Using the secondary micro-projections to push or further insert the payload deeper into the skin therefore adds a greater degree of control, precision, accuracy and consistency of delivery of the payload.

Figure 15A is a cross section schematic depicting the secondary micro-projection patch with substrate layer 10, and micro-projections 12, aligned with the payload micro-projection layer containing substrate layer 9, proximal end of micro-projections 1 , distal end 2, and payload 4. The payload is shown as being on either side of the microneedle and covering the central section of the needle, however it will be appreciated that the payload may be equally produced whereby it coats the entire distal region/tip of the microneedle and also entirely shrouds the needle from a region that is adjacent to the proximal end/base of the payload carrying micro-projection.

Figure 15B is a Cross section schematic as shown in Figure 15A showing the secondary sharp tipped projections 12 in a second activated position whereby they have pierced through or passed through vias on the payload patch substrate 9 and sheared off the payload (in this case shown as payload being only on one side of the needle) and thus instantly leaving the payload in the skin once the payload patch and secondary patches are immediately removed from the skin. This method and device allows a payload to be delivered instantly into skin. The delivery is near instantaneous unlike the current state of the art which relies on chemical means of payload release from the microneedles, such as through dissolution and absorption into the local tissues, something that is fraught with issues given the variability in skin moisture level and skin thickness.

The secondary micro-projection patch and payload patch may be two separate patches that are applied one after the other, whereby there are registration means on the payload patch to mate and engage the secondary micro-projection patch to align the secondary micro-projections with the payload micro-projections so as to insert the entire payload microneedle deeper into the skin or to slide adjacent to the payload micro-projection to shear off or detach the payload that is releasably adhered to the microneedle. Preferably the secondary micro-projection patch is adhered or located adjacent to the payload micro-projection patch such that the payload micro-projection patch is pressed into the skin followed by the secondary patch then being folded over and pressed into the skin (using similar registration means described above), to avoid a user from omitting the second step. Alternatively in another embodiment of the invention the two patches may be pre-aligned and mechanically held in place or chemically adhered one above the other with a space between the two such that a single pressing motion leads to the payload patch being partially or fully inserted into the skin followed in sequence by the secondary projection patch which acts to either push the payload microneedles deeper into the skin, or shear the payload off the microneedles and push them into the skin to a depth commensurate with the length of the protruding secondary micro-projections.

Methods of forming the secondary micro-projections as well as the payload microprojection patch may be using any one of a number of techniques including:

Positive Molds:

Positive molds are created based on the desired microneedle geometry. They typically feature protruding structures corresponding to the microneedle shape. Positive molds can be fabricated using techniques such as photolithography, laser ablation, or 3D printing.

Negative Molds: Negative molds are produced by replicating the features of the positive mold. They have recessed structures that match the desired microneedle shape. Negative molds are commonly made from materials like silicone elastomers or metal alloys using processes such as casting or micromachining.

Folding Method:

In the folding method, a flat sheet of material (e.g., polymer) is first coated with the desired microneedle material.

The positive mold is then pressed onto the coated sheet with sufficient force and heat to deform the material and create the microneedle structures.

After the microneedles are formed, the excess material around the microneedles is removed, leaving behind the desired array of microneedles.

Embossing Method:

In the embossing method, the microneedle material is heated and softened to a semiliquid state. The positive mold is pressed into the softened material with high pressure to transfer the microneedle patterns. After cooling and solidification, the excess material is trimmed, and the microneedles are separated from the mold.

Micro-Replication Method:

Micro-replication involves the replication of microneedle structures using a negative mold. The negative mold is filled with the microneedle material (e.g., polymer solution or melt). Excess material is removed from the surface of the mold, leaving the microneedle structures in the negative mold cavities. The microneedles are then released from the negative mold, resulting in an array of microneedles.

After microneedle fabrication, post-processing steps may be performed to enhance the properties of the microneedles. This could include sterilization, surface modification (e.g., coating with drug formulations), or assembly onto backing substrates.

The secondary micro-projection patch is designed to penetrate a soft and flexible substrate or rigid mesh layer and therefore requires specific mechanical properties that enable sufficient penetration depth while minimizing breakages and/or deformation. Some of the key properties of this secondary micro-projection patch are as follows:

Sharpness:

Microneedles should have sharp tips to reduce the force required for penetration and minimize tissue deformation. Sharpness facilitates easy insertion into the soft substrate without causing damage to the micro-projection. However as shown earlier, where a via is created, or a mesh-like structure is created on the substrate the microprojections may be blunt tipped. The micro-projections will have a high aspect ratio whereby the height of these projections is greater than the thickness of the substrate 9/backing layer of the payload patch that it is penetrating. The length may be as long as is needed to further insert/push the payload or a portion of the payload deep into the skin, according to the desired depth. The payload patch may have a thickness of ten’s of micro-meters to several millimetres. The greater thickness will facilitate the incorporation of a mesh-like rigid structure which may have multiple functions, including providing mechanical rigidity to the backing layer, guiding channels or vias that guide the secondary projection toward the payload causing it to be released from whichever substrate it may be bound to and also be pushed further deeper into the skin, and it is emphasised that substrate in this case refers to the micro-projection on which the payload is releasably or semi-releasably adhered (semi-releasably referring to a scenario where the payload adhesion to the micro-projection is a strong adhesion such that it cannot be delaminated from the micro-projection in its entirety and instead the material properties of the payload are such that it is able to fracture or break or release from the bulk payload and therefore release a portion or a majority of the payload from the micro-projection, for example where the Micro-projection may be formed of PMMA and the payload is a combination of a sugar such as sucrose and the active entity, the active entity referring to the vaccine, drug, therapeutic, cosmetic or vitamin/mineral).

Then same applies where the entire micro-projection is the payload, the microprojection may be partially anchored to a mesh or an arm as indicated earlier, to provide mechanical integrity, and it will then either completely or partially detach from the mesh or substrate or arm before it is pushed further deeper into the skin. One example of such system that has been demonstrated to exert these properties is where 60% PVA was used in combination with 40% of an active agent, diclofenac sodium, to produce a solid dissolvable bio-resorbable micro-projection payload. This was anchored using arms as indicated in figure 8, whereby the arms were also produced using PVA and so were compatible with the payload and provided temporary adhesion to the payload yet when the apex region of the micro-projection payload was pressed, the entire micro-projection detached from the arms and was free to move further according to the depth to which it was depressed using the secondary microprojections.

Stiffness: Microneedles need to possess sufficient stiffness to resist bending or buckling during penetration. This ensures that the microneedles maintain their structural integrity and penetrate the substrate layer effectively without bending or breaking. For microneedles that are to be coated, or have a payload reversibly positioned on or attached to it, this property may be readily achieved using one or more combination of materials listed earlier. For the purposes of the secondary microprojection however, in a further embodiment of the invention it may be preferable to have micro-projections that are capable of deforming upon impact with a substrate. For example, in Figure 13 we show blunt projections 11 of the secondary microprojection patch having passed through the substrate 9 of the payload micro-projection patch such that it is able to mechanically detach part or all of the payload layer 5 from the microneedle with apex 1 and distal tip 2. However, this requires precision alignment such that the blunt projections 11 do not come to rest on top of the apex 1 of the payload patch. In the event that the blunt projections 11 are deformable, flexible, and malleable, there is no longer a need to design the patch with precision alignment. Instead the blunt projections 11 of the secondary micro-projection patch, or indeed sharp tipped micro-projections 12 as shown in Figure 11 , can be formed to be of a micro-projection density that is greater than the micro-projection density of the payload micro-projection patch, such that irrespective of the alignment between the payload micro-projection patch and the secondary micro-projection patch, some of the microprojection patches of the secondary micro-projection patch will insert alongside the micro-projections of the payload patch, and some will impact the apex region of the payload micro-projections. If the secondary micro-needle patches were mechanically stiff, they would prevent any of the secondary micro-projection patches from entering through the substrate 9, and instead the two patches will remain separate. However, with deformable/flexible micro-projections on the secondary micro-projection patch those micro-projections hitting the apex of the payload micro-projection patches, the secondary micro- projection patches will bend or deform or enter the substrate 9 at an angle, such as the angled secondary micro-projection 13 patch shown in figure 12. This will act to facilitate the mechanical shearing of the payload and its further travel through the skin according to the length of the micro-projections or the secondary micro-projection patch. A combination of high and low molecular weight polymers cited earlier potentially with plasticisers may be used to achieve the requisite levels of flexibility of the secondary micro-projections. The requisite level of flexibility is such that the secondary micro-projection is able to deform/bend when it comes into contact with the apex of the payload micro-projections or arms 8, or interlinks 6, yet still maintain sufficient mechanical strength to be able to shear or detach the payload from the payload micro-projection patch; this will also be a function of the excipients utilised in the payload. In a Further embodiment of the invention the secondary microprojection patch may be specifically designed to be of a higher density i.e., more microprojections, than the payload micro-projection patch. The purpose of this will be to have secondary micro-projections which simply create pores in the skin causing skin damage and inflammation to facilitate a higher or stronger immune response where the payload is a vaccine or an antigen designed to be delivered to determine allergy to a given substance without having to use large amounts of the allergen thus making it far safer to conduct the allergy test, and with respect to a vaccine potentially achieving larger dose-sparing from an enhanced immune response. One other means of achieving this inflammatory response using a payload micro-projection patch alone would be to selectively coat/apply payloads to micro-projections on the payload microprojections, and leave surrounding micro-projections free of pay-load where they would act not to deliver a payload but to inflict trauma to the skin and hence initiate an inflammatory response peripheral to the region where the payload has been delivered into the skin.

Inflammation resulting from microneedle-induced skin damage can contribute to a better immune response, particularly in the context of vaccination. The inflammatory response triggered by microneedle insertion serves as a natural mechanism to recruit immune cells, enhance antigen uptake, and activate immune pathways, ultimately leading to an improved immune response to the administered vaccine antigens. Here's how inflammation from microneedle skin damage can enhance the immune response: Activation of Immune Cells: Microneedle-induced skin damage triggers the recruitment and activation of immune cells, including dendritic cells, macrophages, and neutrophils, to the site of injury. These immune cells play essential roles in antigen presentation, cytokine production, and immune activation.

Antigen Uptake and Presentation: Inflammatory signals generated at the site of microneedle insertion facilitate the uptake and processing of vaccine antigens by antigen-presenting cells (APCs), such as dendritic cells. APCs capture antigens released from the microneedles and migrate to nearby lymph nodes, where they present the antigens to T cells and initiate adaptive immune responses.

Enhanced Immune Activation: The presence of inflammatory mediators, such as cytokines and chemokines, at the site of microneedle-induced skin damage promotes the recruitment and activation of immune cells, leading to a more robust immune response. This enhanced immune activation contributes to the generation of antigenspecific T cell and B cell responses, crucial for vaccine-induced immunity.

Increased Antigen Persistence: Microneedles can promote the prolonged presence of vaccine antigens in the skin, creating a depot effect that enhances antigen exposure to immune cells and extends the duration of immune activation. This sustained antigen presentation contributes to the development of long-lasting immune memory and improved vaccine efficacy.

Induction of Innate Immune Memory: Inflammatory signals generated by microneedle- induced skin damage can induce innate immune memory, also known as trained immunity, in skin-resident immune cells. This phenomenon primes immune cells to mount more robust and rapid responses upon subsequent encounters with the same or related antigens, further enhancing vaccine-induced immunity.

Overall, the inflammation elicited by microneedle-induced skin damage plays a crucial role in enhancing the immune response to vaccines by promoting antigen uptake, immune activation, and the generation of long-lasting immune memory. Harnessing the inflammatory properties of microneedles can contribute to the development of more effective and efficient vaccine delivery strategies using this dual secondary micro-projection patch approach, or redundant (non-payload coated/loaded) microprojection approach.

Flexibility: While stiffness is important, the microneedles will also exhibit some degree of flexibility to accommodate the curvature of the skin and substrate surface. Flexibility allows the microneedles to conform to irregularities in the substrate layer, enhancing their ability to penetrate evenly and consistently. This level of flexibility is minor, and not of the order described in the immediately preceding paragraph where the flexibility is engineered to achieve a specific mechanical function, one that is counterintuitive to microneedle manufacture and administration.

Strength: Microneedles must have adequate strength to withstand the forces exerted during penetration without fracturing or shearing. High strength prevents microneedles from breaking or deforming under mechanical stress, ensuring reliable and successful penetration into the soft substrate. Whilst an embodiment of the invention calls for secondary flexible micro-projections, the strength must be maintained to ensure the secondary micro-projections do not fracture or shear. In some cases it may not be entirely possible to produce secondary micro-projections of the requisite aspect ratio that do not fracture for example, in which case these secondary micro-projections may be also produced using bio-resorbable materials such that any fractured remnants in the skin do not pose a toxicity issue. In a further embodiment of the invention the secondary micro-projection may also partially or wholly contain the payload which is designed to shear upon insertion into the skin, whereby the first payload microprojection array is intended to form pores in the skin via which the secondary microprojections may seamlessly enter the skin. This may be necessary where it is not possible to produce payload micro-projections of the requisite mechanical strength to be able to pierce the skin, thus materials of very high mechanical strength are used as the payload micro-array projection but in this case without any payload, and the secondary micro-projections which have less mechanical strength are able to penetrate the skin alongside the pores created by the pay-load micro-projections, and in this case the secondary micro-projections have less mechanical strength which also facilitates their fracture leading to remnants in the skin. Whilst this is not shown in the schematics, in Figure 10, secondary micro-projection 11 , and in Figure 11 , secondary micro-projection 12 could be entirely or the distal portion toward the blunt or sharp tip, composed of the payload, designed to fracture and remain in the skin.

In a further embodiment of the invention the payload may be present within the substrate layer, within the mesh structure for example, or in the vias in the substrate layer, as discrete particles, agglomerates, complexes of excipients and active agent for example, or an integral part of a continuous homogenous or heterogenous medium such as a dispersion/mixture or (viscous) solution or medium within a matrix composed of bio-resorbable materials. The first set of micro-array projections would act to pierce holes in the skin and the secondary micro-projections would push the payload through the substrate and via the piercings alongside the first set of micro-array projections, into the skin. In this case the payload would be deemed to be at the same level as or above the apex of the payload micro-projections, in the substrate 9 layer. Whilst it has been broadly discussed that the payload must be composed of bioresorbable materials, this is not necessary where a critical illness is being addressed or indeed where the material is inert but not necessarily bioresorbable. Examples of this include but are not limited to the following whereby the martials would generally remain in the tissue or skin after the active agent has been released: Polyethylene glycol (PEG) Polyvinyl alcohol (PVA) Polyvinylpyrrolidone (PVP) Polycaprolactone (PCL) Poly(methyl methacrylate) (PMMA) Poly(ethylene-co- vinyl acetate) (PEVA) Poly(acrylic acid) (PAA) Polyurethane (Pll) Poly(ethylene oxide) (PEG) Poly(ethylene terephthalate) (PET)

One of the key benefits of using such materials as part of the payload formulation, in particular for delivery of actives to an organ or tissue is that drug release can be modulated to be over prolonged periods of weeks or months, for example in the case of oncology where following surgery it may be beneficial to insert a payload containing active into local tissue inside the body from which drugs of chemotherapeutic agents are gradually released over sustained periods to avoid the need for long term systemic drug delivery and its associated side effects and adverse events. Whilst there are implants that are positioned inside tissues such as the brain and within blood vessels by way of stents for drug elution, there is a significant benefit to being able to distribute the payload over a broader area as can be achieved using multiple micro-projections especially where organs and tissues are concerned that have the propensity for cancerous cells to regrow, thus enhancing the efficacy of the implanted payload.

Adhesion: Microneedles should adhere securely to the patch backing or substrate surface to prevent detachment during insertion. Strong adhesion ensures that the microneedles maintain their position and alignment during penetration, facilitating uniform and controlled delivery of drugs or vaccines. Whilst this is the case for the payload micro-projection patch, where the payload is not the micro-projection itself, this invention teaches that the micro-projection should be able to delaminate, fracture or dissociate or breakaway from the substrate where the micro-projection is composed to be the payload.

A variety of techniques or devices may be used to apply the micro-projections and associated payloads into the skin including but not limited to the following (including application to internal organs and ocular delivery and to internal tissues, all defined by the term ‘skin’ for the Purposes of this application):

Manual Application: Directly pressing the microneedle patch onto the skin using hand pressure.

Spring-Loaded Applicators: Devices with a spring mechanism to ensure consistent and controlled insertion of microneedles into the skin.

Microneedle Rollers: Rollers equipped with microneedles that are rolled across the skin's surface to create micropores.

Patch Adhesive Rollers: Rollers designed to adhere microneedle patches securely onto the skin surface.

Stamping Devices: Devices that stamp or press microneedles into the skin in a controlled manner.

Pen Microinjection Devices: Devices capable of injecting microneedles into the skin at specific depths and angles such as devices used to inject liquid drugs such as insulin etc.

Pneumatic Devices: Devices that use air pressure to insert microneedles into the skin quickly and precisely.

Microneedle Patches with built-in Applicators: Microneedle patches designed with built-in applicators (such as a dome that inverts from convex to concave) for easy and accurate placement on the skin.

Figure 15C depicts a schematic of Payload 4 on distal tip 2 of the payload microprojections with distal 2 region and substrate 9, shown as shrouding the entire distal half of the micro-projection. It will be appreciated that equally the payload micro-project tip 2 may protrude from the tip of payload 4, in particular where higher mechanical integrity is required to insert the payload micro-projection into the skin. The payload is releasably held in place such that it may be mechanically sheared or moved off the tip of the micro-projection on insertion into the skin using the secondary micro-projection patch as shown in figure 15B, or it may be that a secondary micro-projection patch is not needed as the formulation composition/excipients that are used for the payload 4 are such that upon insertion into the skin the distal tip of the payload micro-projection pushes through the payload as it is forces through the skin, and in doing so it fractures or dislocates the payload shroud off the distal tip of the micro-projection, therefore not requiring a secondary micro-projection patch; or the simple pressure created by the skin surrounding the payload, which is designed to have a conical type shape whereby there is a region such as the base that is larger than the payload micro-projection so that the payload 4 is retained preferentially by the skin. Whilst the schematic depicts a shroud completely enveloping the distal tip of the payload micro-projection it will be readily appreciated that the payload may preferably only partially surround the distal tip of the payload micro-projection. The key to achieving a payload that is releasably coated to the micro-projection is to ensure the payload is not dried entirely directly on the micro-projection on which it is intended to be loaded for insertion into the skin, and instead the payload is formed in a separate mold, and once it is partially or fully dried the payload micro-projection is applied to the mold fitting the distal tips 2 of the payload micro-projections into the payload 4, such that the even if a final drying stage is required there is no or minimal contraction during drying leading to mechanical restraint and tightness of the payload onto the payload micro-projection such that it cannot be released without a secondary micro-projection, or that there is not any high degree of intimate physical adherence as solvent evaporates off, between the payload and the payload micro-projection. Alternatively, as depicted in Figure 15D, there may be a pierceable/penetrable barrier 16 between the payload 4 and the skin, acting to physically restrain the payload 4 on the tips 2 of the payload micro-projection, such that the payload 4 cannot become dislodged or fall off the payload micro-projections during storage or transportation up until after use. Such a penetrable barrier may be simple sugar paper or a thin film such as the oral thin films that readily disintegrate, or a thin polymer film using any one of the materials described earlier.

The subject on whom this type of device is applied may be a human or animal, and the term skin has been used broadly throughout this patent to denote superficial skin, mucosa, including oral mucosa and gums, internal organs and tissues as accessed through surgery. The term payload has been used to denote drugs, cosmetic agents, particles, vaccines, minerals, supplements, and therapeutics and inert agents as may be required to impart some type of benefit when inserted into the skin, whether therapeutic, structural/mechanical or other. The subject may also be an inanimate object for cosmetic purposes or may be vegetation, for example to load an agent across a large area for testing or other purposes, such as across the stem or leaf of a plant.

It will be appreciated that the numerous features described above and/or illustrated herein are set forth by way of example and are not intended to limit the scope of the invention. Numerous alternatives, variations, modifications, additions, and omissions, to those examples will be apparent to a person skilled in the relevant art. It is envisaged that features from different embodiments may be brought together, without adding to the scope of the invention. In addition, the order of any features in the form of method steps or sequences in the description, claims and/or drawings herein is not intended to require that order of performance unless a particular order is necessary for technical reasons. Multiple features in a single claim herein may be so combined in that claim for, for example, fiscal, not technical reasons and so such combined features are not necessarily intended to form a whole inseparable technical concept. Thereby, in the claims set forth, it is intended that claim features may be exchanged between, or extracted from, claims containing other features without broadening the scope of the invention, or causing a so-called intermediate generalisation.

Claims

1. A device suitable for the delivery of an active agent, into or onto skin, mucosa, tissue or the like, the device comprising a primary substrate including one or more primary micro-projections, for providing said agent, and one or more secondary micro-projections, the or each respective pair of primary and secondary micro-projections being co-operable in use such that the secondary micro-projection of the pair acts on the primary micro-projection of the pair to urge the primary micro-projection of the pair into, or further into the skin.

2. The device of claim 1 wherein said one or more primary micro-projections comprises a primary array of micro-projections, and said one or more secondary micro-projections comprises a corresponding secondary array of micro-projections.

3. The device of claim 2, wherein the micro-projections of the primary array are detachable from the primary substrate under the urging action of the secondary array.

4. The device of claim 3 or 4, wherein the primary micro-projections are formed substantially or wholly from the material of the active agent and are formed on a primary substate.

5. The device of claim 4 wherein the micro-projections are releasably adhered or releasably anchored to the primary substrate.

6. The device as claimed in any one of the preceding claims 2 to 5, wherein the primary array of micro-projections are constructed from a skin-penetrable material detachable with the primary micro-projections in use.

7. The device as claimed in any one of the preceding claims 3 to 5, wherein the primary micro-projections have a length suitable for complete insertion into the skin without protrusion above the skin after said detachment.

8. The device as claimed in any one of the preceding claims, wherein the secondary micro-projection(s) provide mechanical support to facilitate the insertion of the primary micro-projection(s) and have a length corresponding to the depth of required insertion of the primary micro-projections.

9. The device as claimed in any one of the preceding claims, wherein the primary and secondary arrays are aligned or alignable to provide said co-operation, for example by means of mechanical registration.

10. The device as claimed in any one of the preceding claims 1 to 9, wherein the secondary micro-projection(s) are formed to pierce through the substrate without vias.

11. The device as claimed in any one of the preceding claims, wherein the secondary micro projection(s) have a predefined length to allow for delivery of the active agent to a precise depth.

12. The device as claimed in any one of the preceding claims, wherein said active agent is in the form of a discrete particle, an agglomerate, combined with an excipient, an encapsulation of a solution or combined into a bio-resorbable material.

13. The device as claimed in any one of the preceding claims, wherein the secondary array of micro-projections are blunted to assist said urging.

14. The device as claimed in any one of the preceding claims, wherein the primary and secondary micro-projection(s) are pre-aligned.

15. The device as claimed in any one of the preceding claims 1 to 12, wherein the secondary micro-projection(s) are sharp-tipped, and the primary microprojection include vias through which the secondary micro-projections can penetrate in use.

16. The device as claimed in any one of the preceding claims, wherein the primary micro-projections are coated with the active agent over their entire length.

17. The device of claim 1 or 2, wherein the active agent is carried on the primary micro-projections and the secondary micro-projections are arranged to shear the agent off the primary micro-projections in use.

18. The device as claimed in any one of the preceding claims, wherein the active agent is a therapeutic drug, vaccine, cosmetic agent, vitamin, or nutrient for transdermal or mucosal delivery.

19. A method for delivering an active agent onto or into the skin, mucosa, or tissue or the like, the method comprising the steps of:

(i) applying to the skin a primary substrate having one or more primary micro-projections for providing the agent; and

(ii) applying to the or each primary micro-projection, a co-operable secondary micro-projection, and urging the same to push the primary micro-projection(s) into, or further into the skin.

20. The method of claim 19, wherein said one or more primary micro-projections comprises an array of primary micro-projections formed on a substrate and said secondary micro-projection comprises a secondary array of micro-projections co-operable with the primary array.

21. The method of claim 20, wherein the micro-projections of the secondary array are pierced through the substrate and thereby push the micro-projections of the primary array more deeply into the skin.

22. The method of claim 20, wherein the micro-projections of the primary array are formed wholly or substantially from the active agent and the micro-projections of the secondary array have a length determined by the depth of desired delivery of the active agent.

23. The method of claim 20, wherein the step of applying the secondary microprojections is a single pressing motion.

24. A micro-needle device when used in a method according to any one of claimsl 9 to 23.

ANY REFERENCE TO FIGURE 5 IN THE INTERNATIONAL APPLICATION WILL BE CONSIDERED NON-EXISTENT (ART. 14(3))