WO2025238529A1

WO2025238529A1 - Device with removable integrated carriers for delivery of agents into the skin

Info

Publication number: WO2025238529A1
Application number: PCT/IB2025/054980
Authority: WO
Inventors: Dewan Chowdhury
Original assignee: Individual
Current assignee: Individual
Priority date: 2024-05-16
Filing date: 2025-05-13
Publication date: 2025-11-20
Anticipated expiration: 2026-11-16

Abstract

Disclosed herein is a device for delivering agents, such as therapeutic agents, into the skin of a patient, the device comprising carriers (3) associated with a carrier supporting substrate (5), wherein each carrier (3) is releasable from the substrate (5) and wherein each carrier (3) is capable of penetrating said skin to administer the agent into the skin. The substrate may include dispensing arms (11), which are used to force each of the carriers (3) into the skin.

Description

Device with removable integrated carriers for delivery of agents into the skin

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 their 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 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 micrometres to a few millimetres, 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 carrier 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 microneedle patches 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 carrier 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 carrier 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 carrier 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 needle-based 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 needle-phobic or require frequent injections. Carrier 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 carrier 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 carrier.

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 carrier 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 carrier, 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 carrier 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 carrier-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 build-up 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.

Improper and inconsistent dosing:

Microneedle patches have evolved to require sophisticated applicator devices to ensure the microneedles can penetrate the skin to the requisite depth and consistently and reproducibly. Inserting a single needle inside the skin is relatively easily achieved but a bed of needles which generally numbers from a few needles to several thousand needles over a few square centimetres area of skin leads to enormous inconsistencies in drug delivery due to the bed of nail effect and inconsistency in the number of needles that penetrate the skin and their ability to remain inside the skin to the same depth. This inconsistency alone is adequate to render microneedle patches inadequate for therapeutic use, and therefore be of no practical utility in drug delivery. Many patches, as discussed earlier, require significant residence times and improper skin penetration in the skin will alone impede consistency of drug delivery.

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 carrier-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 carrier 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 carrier 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 carrier 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 carrier 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 carrier 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 microneedle-based drug delivery systems while minimizing the duration of skin contact.

Summary of the Invention

This invention describes devices and methods for the rapid or instant delivery of a drug, vaccine, therapeutic, neutraceutical or cosmetic agent, hereinafter referred to as ‘agent or payload’, through the skin or mucosa, internal or external to the body, hereinafter referred to as skin, using a solid or semi-solid, liquid or combination thereof, hereinafter collectively referred to as ‘carrier’. The invention overcomes the issues described earlier with respect to prolonged skin residence time of microneedles and inconsistencies in the delivery of agents 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), for the purposes of this description hereinafter referred to as ‘skin’, without the need for any prolonged residence time of a device, patch or microneedle system on the skin, other than the time taken to press and apply a device to the area where the agent is intended to be delivered. For the purposes of this description the entity that is to be inserted into the (skin) mucosa, tissue, or organ of a human or animal subject, (and equally applicable to inanimate objects for the delivery of agents, or plants), is referred to herein as a ‘carrier’. The carrier may be solid, semi-solid, have smooth surface profiles, jagged or rough surface profiles, sharp or blunt tipped, shaped as a needle-like structure, star shaped structure, cylindrical, conical, rectangular, high aspect ratio, porous, semi-porous, or other type of substrate that has the ability to carry a payload that may be in liquid, solid, semi-solid, or gaseous form, that is designed to be delivered to or through the skin.

The carrier may be constructed, moulded, casted or assembled/formed on a substrate where it is semi-permanently and/or releasably held from which it is inserted in the skin. An auxiliary arm is used to place pressure on the carrier forcing it through the substrate, out of the substrate, into the skin. The auxiliary arm having sufficient mechanical properties to exert the requisite force to enable the carrier to be pushed through the substrate and skin to the required depth. There may be one or more carrier. The carrier may be microns in diameter or length, up to several hundreds of micrometres or millimetres in length. The carrier is located within a substrate or positioned on a substrate from which it can be readily forced into the skin to the desired depth. The carrier may be produced within the substrate or separately prepared and placed on the substrate.

The carrier properties dictate its ability to penetrate the skin, in combination with the geometry of the auxiliary arm which can influence the force per area that is exerted and hence affect the type of geometry required to insert the carrier into the skin. The substrate containing the carrier is also inter-related and will impact the forces required to push the carrier through the skin. Furthermore the distance travelled by the auxiliary arm will also affect the efficiency and efficacy and reproducibility with which the carrier can be inserted inside the skin as described below. The carriers may be interlinked to allow them to be removed from the skin if required.

The invention can be put into effect in numerous ways, examples of which are illustrated in the drawings, wherein:-

shows a carrier and substrate;

shows a modified carrier and substrate;

shows a plan view of a substrate;

shows an administering arm for cooperation with the substrate shown in ;

Figs 4B, C, D and E show an assembly of the components of Figs 1 or 2, 3 and 4A to form a microneedle device, in various states of use;

Figs 5 and 6 show modified carriers;

Figs 7 and 8 show modified administering arms;

Figs 9 and 10 show further modified carriers;

depicts a carrier in use partially inserted into the skin;

show an alternative microneedle device illustrated in use;

shows a modification for latching parts of the device during use;

Figs 14A,B and C show different views of an alternative arrangement of a microneedle device

Figs 15 and 16 show alternative carrier arrangements;

Figs 17A and B show alternative arrangements for delivering more than one agent.

Detailed description of Figures

Embodiments of the invention are described below in more detail with reference to the drawings

is a schematic of a generic shaped (primary) carrier 3 and carrier substrate upper face 1, having carrier substrate wall 2 and carrier substrate tip or distal portion 4, and substrate base 6, and distance between carrier and skin substrate region 5. Substrate region 5 could be a solid or semi-solid material produced from the same or different material as the rest of the substrate and the distance between substrate distal region 4 and substrate base 6 dictates the distance the carrier 3 must travel to reach the skin which would be below, adjacent to, or in contact with substrate region 6. This distance is significant as it dictates the distance of travel of an auxiliary arm (not shown in this figure) whereby it would be beneficial for the distance of travel to be sufficient to generate sufficient acceleration on the auxiliary arms to enable the carriers to be forced into the skin to the desired depth. The distance of travel is at least 50 micrometres and up to several 10’s of millimetres. Preferably the distance of travel is between 100 micrometres and 5mm. A very short distance of travel would render this device inoperable since the forces required to attain sufficient acceleration to push the auxiliary arms against the carriers and through the substrate region 5 and substrate base 6 and into the skin would not be attainable, requiring multiple presses and leading to inconsistencies in the delivery of the carrier through the skin. In the case of the use of auxiliary energy such as a compressed gas the substrate region 5 thickness is sufficient to ensure the auxiliary energy can be transferred to the upper surface of the carrier 3 such as to cause it to accelerate through the substrate region 5, which may be hollow (as depicted in subsequent figures). This distance is preferably greater than 100 micrometers and less than 20mm in the case of the use of auxiliary energy such as a compressed or pressurised gas.

The shape of the carrier may be cylindrical, conical, star shaped, or any shape that has the ability to penetrate the skin, with suitable exertion force using an auxiliary arm or auxiliary energy. The auxiliary arm however need not be restricted to a physical implement, it may also be gaseous for example, whereby the gas is compressed and applied above the carriers sealed with the substrate in a format that forces the carriers via the substrate through the skin to the desired depth. One major advantage of this method is that the compressed gas, (auxiliary gas), unlike injector guns that accelerate particles at high speed through the skin causing a lot of collateral damage to tissues, will be focused on precise regions above the carriers thus only forcing the carriers into the skin without collateral damage.

Aspect Ratio: The aspect ratio refers to the ratio of carrier length to width. A higher aspect ratio typically corresponds to longer and thinner carriers. An ideal aspect ratio balances the need for sufficient penetration depth with mechanical stability and manufacturability. For most applications, carriers with aspect ratios ranging from 2:1 to 6:1 are commonly used. However, in this case the aspect ratio may be 1 or less, in that the carrier does not depend on its height to be able to penetrate the skin, and instead it depends on the auxiliary arm length or auxiliary energy. This is impossible to achieve with conventional microneedles (where the needles are intimately/physically attached to the substrate surface thus the distance of travel into the skin is limited and precluded by the base of the needle patch) and allows the superficial delivery of agents via carriers which may be beneficial for therapeutic or cosmetic purposes.

Shape: carriers can have various shapes, including conical, pyramidal, cylindrical, or blade-like shapes. Conical or pyramidal shapes are often preferred due to their ability to create precise microchannels in the skin with minimal trauma. Conical carriers provide a gradual penetration profile, reducing the risk of skin damage or discomfort. However, in this invention a simple cylindrical carrier would also seamlessly penetrate the skin given the forces applied to insert the carrier into the skin is not restricted to the height of the carrier, and instead it is a function of the mechanical strength and height and aspect ratio of the mechanical auxiliary arm.

Size: Carrier size is typically characterized by dimensions such as length, width, and base diameter. The size of carrier depends on the target depth of penetration, skin thickness, and the mass of drug or vaccine or other agent to be delivered. Carriers can 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 carriers. Smaller carriers may be suitable for shallow skin penetration or sensitive areas, while longer carriers are required for deeper delivery or thicker skin. A benefit of this invention is the ability to precisely, instantly, deliver multiple numbers of very small carriers to any precise depth within the skin, thus allowing for precision delivery as well as minimal trauma to the skin. This is not possible with conventional microneedles where the microneedle (the equivalent of the carrier in this invention) must dissolve in the skin or release its coating into the skin. This takes some time and leads to inconsistent delivery of the agent. This invention allows the precise delivery of multiple carriers of a size as little as 10 micrometres or more with a density of up to 4 or more carriers per area of 30 micrometres by 30 micrometres (900 square micrometres). This can be highly advantageous for the treatment of skin scars and pigmentation as well as therapeutic delivery.

Carrier Tip Sharpness: The sharpness of the carrier tips plays a crucial role in facilitating smooth penetration into the skin with minimal force. The carrier tip is herein defined as the leading edge that penetrates the skin. Sharp tips reduce the insertion force required and minimize tissue damage, resulting in a more comfortable and efficient delivery experience for the subject. Carriers with tip radii ranging from a few micrometres to a few tens of micrometres are typically preferred for skin delivery applications. Note that tip sharpness here equally refers to carriers that are in the shape of particles of uniform or random geometry with jagged edges whereby the leading edges are herein referred to as the tips.

The materials of construction of the carriers may include any of the materials listed below. It will be noted that the carrier materials may be both biodegradable, bioresorbable or non-biodegradable/resorbable. In the case of the latter it may be preferable to remove the carriers from the skin after the agent has been delivered as described in subsequent sections:

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

Stainless Steel: Stainless steel carriers 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 carriers provide sharp tips and can penetrate the skin effectively for delivery of an agent that is coated on it. Medical grade stainless steel may reside indefinitely in the body.

Polymers (e.g., Polydimethylsiloxane - PDMS): Polymers like PDMS offer flexibility, biocompatibility, and ease of fabrication, making them suitable for carrier production. PDMS carriers can be molded or cast using soft lithography techniques, enabling the creation of customized carrier arrays with varying shapes and sizes.

Biodegradable Polymers (e.g., Polylactic Acid - PLA): Biodegradable polymers like PLA degrade in the body over time, eliminating the need for carrier removal after drug delivery. PLA carriers 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 carrier matrices. Hydrogel carrier 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 carrier fabrication. Silk carrier can be produced using techniques such as microfluidics or micromolding, offering controlled drug delivery and minimal tissue damage.

Glass: Glass carrier 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 carrier geometry and dimensions.

Sugar (e.g., Dextran or Sucrose): Sugar-based materials can be used to fabricate dissolving carrier that dissolve upon insertion into the skin, releasing encapsulated drugs or vaccines. Sugar carrier 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 carrier fabrication.

Pharmaceutical Excipients: Any excipient that is approved or can be approved as an injectable grade material, or able to reside in the skin without long term adverse effects may be formulated into a carrier, based on formulation compositions well established in the art. A combination of polymers and porous matrices may be used to deliver an agent using the desired release kinetics, either instantly or over a prolonged period of time which may be hours, days, weeks or months.

Furthermore, 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 carrier due to their biocompatibility, water solubility, and ability to form hydrogels, which aid in carrier insertion and drug delivery.

Gelatin: Gelatin is a biodegradable protein derived from collagen and is commonly used to fabricate dissolving carrier. 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 carrier 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 carriers. 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 carrier 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 carrier. 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 carrier 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 carrier 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 carrier 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 carrier 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 carrier 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 carrier that adhere to the skin surface, release drugs in a controlled manner, and eventually biodegrade within the body.

A combination of the above could be used to formulate a carrier that provides specific rates of release of the agent, such as surface eroding polymers, e.g., Polyanhydrides: these are a class of biodegradable polymers characterized by anhydride bonds that connect repeat units of the polymer backbone chain. Their main application is in the medical device and pharmaceutical industry. In vivo, polyanhydrides degrade into non-toxic diacid monomers that can be metabolized and eliminated from the body.

The active agent that is loaded into the carrier(s) may be drug, vaccine, a cosmetic agent, vitamins, nutrients, minerals, immune activating compounds, etc., each which will be formulated in a manner that renders it compatible with the carrier without compromising the mechanical integrity of the carrier which is required to be sufficiently strong to be able to penetrate the skin. However a benefit of these carriers is that given they are secured in chambers, the carriers may be porous materials or of a porous construct, the methods of preparation of which are well established in literature, and then infused with a liquid or non-solid active such as a molten wax, oil or other on solid material, which diffuses out of the carrier once delivered into the skin.

The carrier substrate may be produced from any one or combination of the materials listed above that are used for the carriers. Polymers and gels such as alginates and silicones and polyurethanes have the advantage of being soft materials which will allow the carrier to pass through the substrate without needing it to flex, simply by creating a cavity within the material as it is pushed through the substrate by the kinetic energy imparted upon it by the auxiliary arm(s).The distance between the distal region of the carrier 4 and substrate base will be sufficient to allow the required momentum and kinetic energy on the carrier to be attained that allows the carrier to penetrate the skin to the desired depth. This can be further described as follows:

Pressure applied to auxiliary arm, P = Force/Area (surface area of the upper region of the auxiliary arm into which the user’s fingers or other implement as may be used, come into contact).

Acceleration A of the carrier = Directly proportional to the Force applied, and indirectly proportional to the mass M of the carrier, A = F/M, therefore the smaller the mass of the carrier, and the greater the force applied, the greater the acceleration. The force applied to the carrier in this case is the resultant force based on the skin resistance and the force received on the carrier by the pressure applied to the auxiliary arm. The resultant force is greater than the skin resistance during the piercing, and subsequent penetration of the carrier into the skin. The skin-piercing force may be also described as the surface-breakthrough-force and the resultant force must exceed the surface-breakthrough-force.

The substrate material may be composed of a desiccant material, to provide protection to the carrier which may otherwise lose the sharpness of its leading edge. Most microneedle patches have desiccant incorporate into the packaging to prevent the needle tips from absorbing moisture over their shelf-life, which in the case where the microneedle substrate is produced from drug or dissolvable or swellable material, any damage to the tips can lead to blunting of the tips of the needles thus rendering them ineffective for skin penetration. Desiccant materials include but are not limited to:

Activated alumina
Aerogel
Benzophenone (as anion)
Bentonite clay
Calcium chloride
Calcium oxide
Calcium sulfate (Drierite)
Cobalt(II) chloride
Copper(II) sulfate
Lithium chloride
Lithium bromide
Magnesium chloride hexahydrate
Magnesium sulfate
Magnesium perchlorate
Molecular sieve
Phosphorus pentoxide
Potassium carbonate
Potassium hydroxide
Rice
Silica gel
Sodium
Sodium chlorate
Sodium chloride
Sodium hydroxide
Sodium sulfate
Sucrose
Sulfuric acid
Triethylene glycol
Zeolite

The substrate may also contain chemical stabilisers to prevent any degradation of the active agent that may come into contact with the substrate. One major benefit of this would be that the active agent itself may not therefore require any chemical stabilisers, meaning therefore that it will not be necessary to insert chemical stabilisers into the skin, as many such stabilisers can be toxic and regulatory authorities limit the amounts that can be delivered into the body through the skin. Preservatives for example could also help preserve the antimicrobial integrity of the substrate thus preventing microbial growth. Chemical stabilisers include but are not limited to:

Polymers

Polymers are large molecules composed of repeating units. They can be used as stabilizers for a variety of drug formulations. Polymers can improve the solubility, bioavailability and stability of drugs and also control the release time of drugs.

Cyclodextrins

Cyclodextrins are cyclic sugar molecules that can be used to improve the solubility and stability of drugs. They can encapsulate drugs and protect them from degradation, as well as improve their bioavailability by increasing their water solubility. Cyclodextrins can also be used to modify the pharmacokinetics of drugs, such as prolonging their circulation time in the body.

Chelating agents

Chelating agents are compounds that can bind to metal ions, which can catalyze the degradation of drugs. Chelating agents can be used as stabilizers for various drug formulations, such as parenteral formulations.

Preservatives include but are not limited to:

Benzalkonium chloride
Benzyl alcohol
Parabens
Benzoic acid and sodium benzoate

The methods of incorporation of chemical stabilisers, preservatives or indeed desiccants are not elaborated in this description as these will be obvious to the person skilled in the art of formulation.

is a schematic depiction of but showing the substrate region 5 as having either a hollow region or a pre-cut region without any hollowing or material removal, to allow the free movement of the carrier 3 through substrate region 5 across the substrate base 6 into the skin (adjacent to or in contact with substrate base 6, not shown here). The carrier substrate may be produced from any solid or semi-solid material that allows the carrier to be mechanically restrained in an orientation whereby the leading edge of the carrier faces the skin at least during the point of insertion into the skin. The materials include any one of the polymers or other materials discussed herein. Importantly it is noted that conventional microneedles are configured in a manner whereby they are attached to a substrate and the microneedles are exposed to the atmosphere. These needles therefore do not come into direct contact with any other type of material that may pose an incompatibility issue. In this invention the carriers may be in direct contact with the inner surface of substrate walls 2, hence the substrate material should be composed of a material that does not cause any incompatibility to the agent that is being delivered by the carrier. The substrate may be produced from solid materials such as Teflon and Nylon or softer and potentially compressible materials such silicone and polyurethane. Furthermore, the substrate may be infused with chemical stabilisers such as antioxidants and desiccant material to absorb moisture which could otherwise potentially compromise the carrier mechanical integrity.

is a plan diagram of the substrate upper (outer) face 1 containing registration points 7 which are hollowed sections to allow a registration pillar to be inserted to align the auxiliary arms or gas compartments. Carrier substrate cavities 8 depict the region where the carrier is situated inside the substrate. The registration points 7 are designed to ensure the auxiliary arms (not shown here) are able to seamlessly be aligned and inserted into the cavities 8 to force the carriers out of the substrate when depressed or when the auxiliary energy such as compressed gas is applied.

depicts a schematic cross-section of the auxiliary arm upper surface 9, registration arms with locking means 10, and auxiliary arms 11. Note these are not to scale and the registration arms 9 may preferably be larger than the auxiliary arms 11 and the auxiliary arms are intended to penetrate through the cavities 8 shown in . The registration pillars or arms 10 may or may not have a locking mechanism, although depicted here with a locking mechanism. Preferably the registration arms will have a locking mechanism. Furthermore, the insertion pillars may also have a locking mechanism as well as or in place of the registration arms. This is a fundamentally important part of the invention. A significant issue faced with the insertion of microneedles into the skin is the inability to determine when or whether all the needles have penetrated the skin. In this case, the carriers (the equivalent of the microneedles on a conventional microneedle patch) must exit the carrier substrate and pierce through the skin at least partially or fully util they have reached the desired location within the skin. In the absence of a locking mechanism for the registration or auxiliary arms it becomes guess work as to whether the auxiliary arms have penetrated the correct depth and inserted the carriers to the desired depth into the skin. The latch or locking mechanism is designed to confirm that the auxiliary arm has indeed pierced the skin to the required depth and that the carrier(s) have been delivered. However, one additional issue this method poses is that the force exerted on the skin will lead to an equal and opposite reaction and resultant force which will act to lift the patch off the skin whilst still allowing the registration pillars or and/or auxiliary arms to engage and latch/lock into the carrier substrate. It is therefore preferable for the carrier substrate skin contacting face to have a means of temporarily adhering to the skin with an adhesive force that is greater than the resultant forces arising from the insertion of the auxiliary arm. It will be appreciated that the resultant force that may act to lift the carrier substrate patch off the skin when the auxiliary arm is pushed through the carrier substrate and above the carrier, will be dictated by a number of parameters including the auxiliary arm aspect ratio, flatness or sharpness of the face abutting the carrier, and speed of travel. These forces will be determined on a case by case basis. The adhesion of the carrier substrate skin contact portion may not be a chemical adhesive, since chemical adhesives pose potential skin irritation issues, and may be mechanical adherence, such as through the use of suction cups/vacuum, or pinching the peripheral skin mechanically to prevent the carrier substrate lifting from the skin.

Patent EP 2988 820 (B1) teaches a method of inserting a drug mass into the skin from a drug chamber, containing flexible walls, whereby the drug mass aligns with a mechanical needle and is inserted into the skin alongside the needle, whereby the chamber walls are flexible to allow the distance between the first and second chamber wall to increase to allow the drug mass to pass through. The device described therein relies on a separate needle to create a pore in the skin to allow the drug mass (the equivalent of the carrier in this invention) to pass through into the skin. This invention differs substantially in that it does not require a flexible wall as the carriers can be entirely cylindrical fitting snugly within a cylindrical cavity, and more importantly the carriers themselves are sharp enough to penetrate the skin; the smaller the carrier is the less requirement there is for a very sharp leading edge as micro carriers can have large forces exerted upon them by the auxiliary arm to enable the carriers to be inserted into the skin, unlike the need for a needle as described in EP2988820 where larger pellets/implants are being delivered, and these would require substantial forces as well as a large needle and a substantial pore to be created in the skin to allow the pellet to be inserted inside the skin without causing significant amounts of trauma. Furthermore, in the likes of the invention described in EP2988820, and other patents that describe technologies for inserting a pellet or implant into the skin, those tend to be macro-sized structures which have completely different forces acting and resulting from the methods of use, and such devices generally cater for usually single numbers of pellets or implants to be delivered at a time. Such devices do not have the issue of the resultant forces that may lift the device off the skin and as such they may simply be applied to the skin with a single motion, actuated, and removed. Delivering carriers on this micro-scale brings with it a multitude of challenges and the ability to accurately deliver and retain the carriers in the skin is a crucial element of the invention, since it could mean the difference between having a device with utility and a device that is rendered impractical. Arrays of carriers are important therefore to deliver useful amounts of active agents for therapeutics for example, and a patch-like format is therefore necessary too. Vaccine delivery for example relies on the immune stimulating Langerhans cells to be activated and this requires the vaccine to be delivered in minute amounts interspersed over a large surface area. This invention allows for this to be effectively and efficiently achieved, with close to 100% of the desired dose delivered to the desired regions and depths of the skin. Microneedle patches that deliver such minute quantities on the microscale, across large surface areas are unable to achieve the efficiency of this invention due to the significant limitation imposed by the need for the active agent to dissolve and be released over a period of time that may be between minutes and hours, creating significant inefficiencies and inconsistencies in the dosage delivered, as well as the depth to which the active agent is delivered since over time the microneedles have a tendancy to become dislodged from the skin, especially where the needles are superficially penetrating the skin; deeper skin penetration with longer microneedles does lead to better anchorage on the skin, however this compromises the ability to reach the desired precise depth, such as the depths required to stimulate the Langerhans cells.

, and 4C illustrate a cross section schematic of the impact of the auxiliary arms with and without the temporary adhesion to the skin. Generally, with microneedle patches the adhesive is placed around the periphery of the entire patch. In this invention the carrier substrate patch would benefit from adhesive interspersed between groups or rows of carriers. The figures depict the two-part patch system in the engaged or activated position, whereby shows the auxiliary upper arm surface 9 carrying the auxiliary arms 11 and (locking) registration arm 10 is shown in the fully engaged position whereby it has mated with the carrier substrate upper face 1, auxiliary arm 11 inserted inside the carrier cavity 8, adjacent to the carrier substrate wall 2, through the carrier substrate lower surface 6, through the skin 18, pushing the primary carrier 3 and secondary carrier 16 below the skin layer 18, whereby there is a temporary adhering mechanism 19 surrounding the carrier, which has prevented the carrier substrate from being lifted off the skin and has therefore allowed the carrier to be inserted through the skin 18. In , the temporary adhering mechanism is absent and therefore the carrier substrate lower surface 6 is shown to be a distance away from the skin 18, and the carrier is shown to have exited the carrier substrate and forced out of the carrier substrate by the auxiliar arm and residing between the skin 18 and carrier substrate lower surface 6. In this example the carrier substrate material is depicted as being rigid, though it will be appreciated that the carrier substrate material is preferably flexible in the z – plane to allow it to conform to the contours of the skin, and in this case in the absence of the temporary adhesion to the skin working in synergy with the locking mechanism of the registration pillar or auxiliary column would lead to a much higher exaggerated impact and poor and inconsistent delivery of the active into the skin.

In a further embodiment of the invention the need for a temporary adhesion is eliminated by ensuring the auxiliary arm face 9 is rigid and inflexible at least in the areas directly above the auxiliary arm registration column. The lower section of the column would then abut on to a section of the carrier substrate directly below it between the surface of the bottom of the registration arm and the skin, which is also rigid and inflexible. This will act to ensure regions of the patch containing the registration arms can be used as a platform on which force can be applied to ensure the combined mated patches, auxiliary arm patch and carrier substrate patch, remain firmly on the skin, preventing the entire patch from lifting off the skin, and allowing force to be applied to the auxiliary arms to push the carriers into the skin. Note in this case the registration arms would be independent of the auxiliary arms.

and 4E are cross section schematics illustrating the rigid sections 22 of the auxiliary arm and the rigid section 23 of the carrier substrate, and the flexible wall 24 of the auxiliary arm upper face. is shown in the initial position once the auxiliary arm patch has mated but not yet fully pressed (in the direction indicated by the solid arrows). The flexible region 25 is shown to protrude from the upper face 9 of the auxiliary patch. shows that when the auxiliary arm patch upper face 9 is pressed the carrier 3 exits through the skin and the auxiliary arm upper face comes to rest in parallel to the registration arm upper surface which has come to a stop due to the registration arm having abutted against the solid region 23 in the carrier substrate, which in turn has abutted with the skin surface, thus preventing the auxiliary arm from lifting and ensuring the carrier is pushed into the skin.

It will be further apparent from the schematic in 4E that once the two patches have mated and the registration arms and/or the auxiliary pillars have mated, the auxiliary pillar 9 protrudes from the carrier substrate lower face 6. This acts as a further means of confirming by the user that the carrier has been delivered into the skin in conjunction with the active agent and that no amount of carrier or active agent remains in the carrier substrate patch. The latter is a significant problem with microneedle and transdermal patches in general where there is substantial drug wastage due to inconsistent dosages being delivered, leading to health and environmental hazards. This invention allows for 100% of the desired active agent to be delivered, thus eliminating potentially hazardous waste.

is a cross-section schematic of a carrier 12 shown as have an upper region that is not flat, and is pointed outward.

is a cross-section schematic of a carrier 13 with the upper surface pointing inwards.

is a cross section schematic of a auxiliary arm 14 with the base pointing inward such that it can be releasably secured against the upper surface of the carrier shown in .

is a cross section schematic of a auxiliary arm 15 with the base pointing outward so that it can be releasably secured against the upper surface of the carrier shown in .

is a cross section schematic showing a carrier 3 nestled within the substrate walls 2, and a secondary carrier 16, shown here as a sphere. This embodiment of the invention is designed to allow a second carrier that is completely independent of the first carrier to be delivered into the skin with its own payload. This will allow materials that may be incompatible with the first carrier to be loaded into the secondary carrier for delivery. Furthermore it will allow the secondary carrier to be manufactured completely separate to the primary carrier, and therefore manufactured using conventional large scale processes such as spray drying and sol-gel processes and other processes well established in the art. This is a significant benefit for the delivery of active agents using this carrier-based technology, which otherwise is not possible using conventional technologies.

is a cross section schematic depicting but with a internally facing shoulder 17 at the top of the carrier substrate designed to releasably secure the secondary carrier 16 so that it does not dislodge from the carrier substrate cavity during storage or transit.

is a cross section schematic showing a carrier 3 inserted into the skin 18 whereby the carrier is partially protruding from the skin 18 surface.

is a cross-section schematic illustrating the device in the activated mode whereby the auxiliary upper arm surface 9 carrying the auxiliary arms 11 and (locking) registration arm 10 is shown in the fully engaged position whereby it has mated with the carrier substrate upper face 1, auxiliary arm 11 inserted inside the carrier cavity 8, pushing apart the carrier substrate wall 2, through the carrier substrate lower surface 6, through the skin 18, pushing the primary carrier 3 and secondary carrier 16 below the skin layer 18.

is a cross sectional schematic depicting one of many techniques that could be used to latch the auxiliary arm patch with the carrier substrate patch. Latch points 20 are depicted within the carrier substrate, and an auxiliary pillar latch 21 is also shown which will allow the auxiliary pillar to also be latched to the carrier substrate once the two patches have been activated by mating them. This latching mechanism also serves one further critical embodiment of the invention, and that is feedback or confirmation to the user that the carrier has been delivered into the skin and that the patch may now be disposed. Regulatory requirements for drug and vaccine delivery are very stringent and the need to provide a means of determining that the requisite dose has been delivered is a requirement for injectables. It is near impossible to determine this for a microneedle patch whether there are dozens to thousands of microneedles on a patch. This invention allows the user to determine that the full dose has been delivered by virtue of the two patches engaging, mating and latching. When the user feels the halves have clicked together and on removal from the skin when the combined patch is checked to ensure the two parts do not come apart, it indicates the full intended dose has been delivered. This is not a method that conventional microneedle patches are able to deploy.

Figures 14 A, B and C depict a cross section schematic of a further embodiment of the invention. In this embodiment the system is integrated as a single patch or device (term used interchangeably) 25 and not a separate auxiliary patch and carrier substrate patch. The auxiliary arms 11 are embedded within the single patch 25 which is a flexible material composed of any one or combination of materials discussed in this patent. The auxiliary arms may be suspended within a polymer which has sufficient pliability to enable the auxiliary arms to transmit pressure onto the carriers 3 and push them through the skin 18, (note the gap seen between the skin 18 and single patch 25 is for illustration purposes only and in practice the two may be in intimate contact as seen in when the single patch is pressed as indicated by the solid arrow). Alternatively, the auxiliary arms may be within a cavity in which they are positioned or sealed but the arms being substantially exposed so when the patch is pressed the auxiliary arms can fully engage with the carrier proximal face and push the carrier through the patch and through the skin, leaving the carriers in the skin as shown in . A major advantage of this approach is that the entire patch will be a single patch and not require a user to engage a separate patch containing the auxiliary arms. Whilst not indicated in this illustration it will be appreciated that the auxiliary arms could be equally latched and locked once the arms have reached the correct depth into the skin. This single patch may be constructed as a single unit or entity in which the carriers and auxiliary arm are loaded or may be produced as separate layers that are adhered to produce a single entity. One further benefit of a single patch construct is that the carrier and active agent may be completely protected from the external environment thus potentially enhancing product stability especially products that are heat, light or moisture sensitive, as the single patch construct could be airtight, insulating and also opaque to protect from light. The carriers could be loaded into grooves, channels, or embedded within the substrate from where it can be forced out and through the skin by the auxiliary arm, which can force a channel through the substrate.

is a cross section schematic illustrating carrier anchors which are accessible following the insertion of the carrier 3 into the skin, such that they may be used to withdraw the carrier from the skin as needed. This may be useful for example with the delivery of contraceptive drugs, where the patient may decide she wishes to plan for conception thus allowing the drug elution to be terminated by withdrawing the carriers 3 from the skin using the carrier anchors as a means of pulling/withdrawing the anchors from the skin. The carrier anchor 26 is attached to the individual carriers via anchor arms 27, the length of the anchor arms 27 being dictated by the depth of penetration of the carriers into the skin. The carrier anchors will reside on the surface of the skin whilst the anchor arms will reside primarily inside the skin. The carrier anchors are able to either cut through the substrate where soft polymers of gels are used as the substrate, or grooves may be present in the substrate to allow the carrier anchors to pass through the substrate and come to rest on the skin surface. The carrier anchors and anchor arms may be produced from any number of individual or combination of materials described within this patent. These may be thin wire like interconnections which can be visible on the skin surface from where they may be used as an anchor point to tug and pull out the carriers from inside the skin. Preferably the carriers in this case will have a shape that is conducive to the least resistance being imparted from the tissues or inner surfaces of the skin, such as having a smooth surface and even longitudinal diameter, for example. The carrier anchors may also be individually located on each carrier, and not be interlinked. This may allow the carriers to be individually removed or partially removed from the skin, for example to reduce the dosage being applied. Furthermore, the anchors may protrude from the skin like hair follicles thus serving as a means of registering that the drug has/is being delivered, as well as a means for removal of the carrier. The carrier anchor material will be of sufficient mechanical strength to resist detachment from the carrier when force is applied to remove the anchor and associated carrier from inside the skin. This may be achieved using one or a combination of the materials that have been listed in this patent.

The secondary carrier offers a number of additional advantages including:

Enhanced Drug Loading Capacity:

The secondary carrier provides additional space for loading with multiple payloads. 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 secondary carrier can protect sensitive drugs or biologics 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 secondary carrier can influence the release kinetics of the encapsulated drug. By modulating factors such as the shape and diameter and the thickness of the secondary carrier walls, we can tailor the release profile to achieve sustained, controlled, or pulsatile drug delivery as desired. The shape can be any shape desired and is not required to have a leading edge that can directly penetrate the skin, which provides great flexibility in the preparation of the secondary carrier, unlike the primary carrier which must have a leading edge.

Increased Surface Area:

The increased surface area of the secondary carrier can provide a larger surface area for drug interaction with the skin. This can enhance drug permeation and absorption, potentially improving the bioavailability and therapeutic efficacy of the delivered drug.

Reduced Insertion Force:

Insertion of a sphere alone into the skin would be near impossible without causing significant trauma to the skin by using significant forces. The use of a secondary carrier adjacent to a leading sharp tipped primary carrier will reduce the insertion force required for skin penetration of the secondary carrier.

Furthermore, materials that may be used for the secondary carrier 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 carrier. It provides mechanical strength, flexibility, and biocompatibility while enabling controlled drug release and dissolution of the carrier 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 carrier, 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 carrier. 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 carrier, 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 carrier. It provides mechanical strength, flexibility, and biocompatibility while enabling controlled drug release and dissolution of the carrier.

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

Polycaprolactone (PCL): PCL is another biodegradable polymer commonly used as a coating material for carrier. 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 carrier, 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 carrier, PEI can improve drug penetration through the skin and enhance the adhesion of carrier 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 carrier, 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 carrier, 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 carrier, hyaluronic acid enhances skin hydration, promotes drug penetration, and improves patient comfort during carrier application.

Polyethylene Oxide (PEO): PEO is a water-soluble polymer known for its lubricating and film-forming properties. When coated onto carrier, 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 carrier, acrylic polymers provide mechanical stability, controlled drug release properties, and protection of the encapsulated drug from environmental degradation.

Additional methods of incorporating an active agent or payload into a secondary carrier include:

Coating Layers:

Drug formulations can be coated onto the surface of carrier 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 carrier surface and encapsulates the drug for controlled release upon insertion into the skin.

Hydrogel Matrices:

Hydrogel-based drug formulations can be applied to carrier to form a hydrated gel layer that adheres to the carrier 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 carrier to form covalent bonds. Chemical crosslinking enhances the stability and durability of the drug-carrier 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 carrier. These polymeric carriers protect the drug from degradation, control drug release kinetics, and adhere to the carrier surface through physical or chemical interactions.

Hydrophobic Interactions:

Hydrophobic drug molecules or lipophilic excipients can interact with hydrophobic regions on the surface of carrier through hydrophobic interactions. This mechanism enables the adhesion of lipophilic drugs or formulations to the carrier surface, facilitating controlled release upon insertion into the skin.

Additional Embodiments of the invention are further described below:

Pitch: The pitch refers to the distance between the centre of each individual carrier within an array of (primary) carriers. 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. This invention overcomes the issue of the bed of nail effect since this type of patch with arrays of cavities in which carriers are contained can be highly densely packed without requiring substantial impact forces to push and force the carriers into the skin for the simple reason that each individual carrier or each row of carrier could be individually pushed into the skin using an auxiliary arm that is either on a motor or on a flexible substrate from which it can be very gradually registered above the patch using the registration points to secure the auxiliary arm patch above the carrier substrate and then gradually each area pressed using either a blunt tipped stick-like implement (not shown here) which presses upon a few auxiliary arms at a time until all the auxiliary arms have mated with the carrier cavities; the registration arm locking mechanism and skin adhesive also act to ensure the auxiliary arm cannot fall off during the skin insertion process, and more importantly the entire auxiliary arm patch must become flat to indicate it is fully mated with the carrier substrate which is also a visual indicator that all the carriers and their associated payloads have been delivered. The pitch of carriers for this device is greater than 10 micrometres where there are two carriers and more preferably greater than 50 micrometres where there are more than 2 carriers. The auxiliary arm may be a single arm which is applied gradually to each carrier to push the carrier into the skin or it may be equal in number to the carriers, and it may be manual or it may be motorised such that it vibrates at the requisite amplitude and frequency to ensure the auxiliary arms have fully mated and penetrated the cavities in the carrier substrate.

Carrier Height: The height of carrier determines the depth of penetration into the skin that is required, to ensure the entire carrier is inserted inside the skin and not protruding from the surface of the skin. The optimal carrier 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 carrier depth of insertion ranges from allowing the carrier to remain partially protruding from the surface of the skin and partially inserted inside the skin, to being inserted deep into the tissue or muscle. The height of the auxiliary arms would therefore be modulated accordingly, as it will also be dictated by the depth of substrate region 5.

Having carriers partially protruding from the surface of the skin may be beneficial for the purposes of extracting materials from the skin for example removal of exudate in traumatised skin such as skin with burns, or removal of analytes from the skin for the purposes of measurement of the concentration of an analyte that would otherwise be present inside the skin or for the purpose of creating a conduit into the skin whereby a patch containing the active agent or payload is applied in a liquid or semi-solid form occluding the regions containing the partially protruding carriers.

Materials that may be used for the auxiliary arm include but is not limited to:

Polyethylene Terephthalate (PET):

PET is a thermoplastic polymer known for its strength, flexibility, and transparency. It is commonly used 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 provide flexibility and durability.

Polypropylene (PP):

PP is a lightweight thermoplastic polymer with excellent chemical resistance and mechanical properties.

Polyvinyl Chloride (PVC):

PVC is a widely used thermoplastic polymer known for its versatility and cost-effectiveness.

Polyurethane (PU):

PU is a flexible polymer with excellent abrasion resistance and mechanical properties.

Polydimethylsiloxane (PDMS):

PDMS is a silicone-based elastomer known for its biocompatibility and flexibility.

Polymethyl Methacrylate (PMMA):

PMMA is a transparent thermoplastic polymer with excellent optical clarity and mechanical properties.

Polyimide (PI):

PI is a high-temperature-resistant polymer known for its thermal stability and mechanical strength.

Metals: A wide range of metals well established in the art can be used to create auxiliary arms.

In a Further embodiment of the invention the carriers may be formulated such that some contain a vaccine and others contain an adjuvant, and others contain a skin irritant or are completely inert. The purpose of inert carriers is to cause skin damage and inflammation in regions peripheral to the regions where a vaccine antigen is delivered to facilitate a higher or stronger immune response. Alternatively this approach may be used 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.

Inflammation resulting from carrier-induced skin damage can contribute to a better immune response, particularly in the context of vaccination. The inflammatory response triggered by carrier 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 carrier skin damage can enhance the immune response:

Activation of Immune Cells: Carrier-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 carrier insertion facilitate the uptake and processing of vaccine antigens by antigen-presenting cells (APCs), such as dendritic cells. APCs capture antigens released from the carrier 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 carrier-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 antigen-specific T cell and B cell responses, crucial for vaccine-induced immunity.

Increased Antigen Persistence: Carrier 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 carrier-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 carrier-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 carrier can contribute to the development of more effective and efficient vaccine delivery strategies using this dual secondary carrier patch approach, or redundant (non-payload coated/loaded) carrier approach.

Strength of Auxiliary Arms: The auxiliary arms must have adequate strength to withstand the forces exerted during penetration without fracturing or shearing. High strength will prevent the auxiliary arms from breaking or deforming under mechanical stress, ensuring reliable and successful penetration into the substrate and subsequently through the skin. In a further embodiment of the invention the auxiliary arm may also partially or wholly contain some payload for delivery into the skin, whereby the auxiliary arm is designed to shear (somewhere along a fracture plane that is created at an appropriate position along the length of the auxiliary arm that is inside the skin at the time of fracture).

Whilst it has been broadly discussed that the carrier 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 (PU)

Poly(ethylene oxide) (PEO)

Poly(ethylene terephthalate) (PET)

One of the key benefits of using such materials as part of the carrier 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 carrier containing active agent 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 carriers 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: The carrier substrate patch may temporarily adhere releasably and securely to the skin to prevent detachment during auxiliary-arm insertion. Strong adhesion ensures that the carrier maintain their position and alignment during penetration, facilitating uniform and controlled delivery of drugs or vaccines.

A variety of techniques or devices may be used to apply the auxiliary arms to the carriers contained within the carrier substrate, and force the 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 auxiliary arm patch onto the skin using hand pressure.

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

Auxiliary arm Rollers: Rollers equipped with auxiliary arms that are rolled across the carrier substrate surface, engaging with the carrier cavities.

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

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 agent delivery purposes, such as across the stem or leaf of a plant.

This invention describes a device for the containment and insertion into the skin of an active agent contained within a primary carrier or a primary and/or secondary carrier. The carrier is releasably stored within a substrate having sufficient integrity and physical barriers or walls to be able to contain the carrier(s) in a releasable manner. The cavity in which the carrier is contained is capable of receiving an auxiliary arm or auxiliary energy through openings of chambers that contain the carriers from whereby the auxiliary arm or energy is able to apply pressure on the carrier sufficient that it forces the carrier out of the substrate and through and into the skin to the desired depth. The opening to the carrier cavity, and the base of the carrier substrate via which the carrier may exit and pass into the skin may or may not be hollow and may consist of a perforation without any material removal, sufficient to enable the auxiliary arm to travel through it and push the carrier(s) into the skin. The carrier substrate may be a flexible material or it may be a rigid but compressible material sufficient that it allows the carriers to expand the walls in the case where the carriers may be conically shaped. Alternatively it may not be flexible or compressible and may be solid and rigid such that the walls collapse or move laterally due to spacings present between the carriers, allowing the auxiliary arm to push the carriers out of the substrate and through the skin. The auxiliary arm abuts the carrier proximal face causing the distal face to pass through the skin. In an alternative embodiment the auxiliary arm may not abut the carrier proximal face and may instead act to compress the substrate material which in turn abuts the carrier proximal face, causing it to subsequently be forced through the carrier substrate base and subsequently through the skin. The carrier substrate wall may be solid, immobile and incompressible, whereby the carrier merely sits within a cavity within the carrier substrate, where it is releasably attached, or where it is adhered directly to the walls, in a releasable manner, whereby some of the carrier material may remain within the walls when the carrier is pushed out of the carrier substrate cavity, whereby the preformed cavity wall dimensions are sufficient to allow the passage of a rigid auxiliary arm. The device may be constructed of two halves, a compressible silicone or other polymer based carrier substrate containing a multitude of cavities each holding carriers for active agents, and a second mechanically strong auxiliary arm patch which registers and mates with the carrier patch, which when applied to the skin and the auxiliary arm patch is pressed until it is flush or in the engaged position with the carrier substrate patch, will have pushed the carriers into the skin of the subject according to the depth defined through a combination of the substrate depth, and auxiliary arm length.

Furthermore, the invention describes methods for administering individual micro-projections into the skin of a subject, of a precise mass, to a precise depth in the skin, and methods for delivering one or more additional carrier containing an active agent whereby the carrier is not required to have any skin-penetrating properties of its own. Methods are also described which allow a user to be able to determine and confirm that individual microneedles or carriers have been delivered into the skin by irreversibly combining two patches, one containing the carrier of the active agent and the second containing the auxiliary arm for delivering or inserting the active agent into the skin. Methods are also described which allow the carriers to be removed or withdrawn from the skin.

In essence this invention describes a radical improvement to the current state of the art of Microneedle patches and provides methods of delivering one or more free standing microneedles (or carriers) into the skin of a subject without the need for any skin residence time of a patch or microneedle insertion device. Microneedles herein defined as carriers having a geometry substantially in the micrometre range, from several micrometres to hundreds of micrometres in one or more dimension.

In a further embodiment of the invention, it may be preferable to deliver a payload that is liquid or semisolid. This may be preferable for a number of reasons, including activation of the payload using specific pH or ionic or other local chemical environmental conditions, the rapid release and absorption of the payload into the microvasculature or interstitial space from which it is absorbed, or for the delivery of a pro-drug that is then converted on mixing with an agent that is carried within the liquid payload. This is not achievable with conventional microneedles or micro-implants given that any system capable of maintaining structural integrity to the extent necessary to enable it to penetrate the skin must be removable from the skin since it must otherwise be able to dissolve and be bioresorbable; if it is able to dissolve then a liquid payload will cause dissolution of the microstructure/needle/implant soon after combining the liquid with the microneedle, assuming the microneedle structure is a honeycomb like structure or similar, that contains voids within its structure that are able to hold a liquid payload. There may be some instances such as in end-of-life scenarios or where the medical condition warrants any intervention that can increase longevity or quality of life, in which case leaving such non-bioresorbable structures inside the skin may be acceptable. The delivery of emergency medicines such as anti-snake venom, epinephrine, or naloxone for example, would require a system that could carry a liquid payload that does not compromise the structural and mechanical integrity of the microneedle, at least for the duration required to insert the needle(s) in the skin. This further embodiment overcomes all these limitations and enables the delivery of a liquid payload into the skin. The liquid payload may be an inert solution, a pro-drug, a pro-drug activator, a medium consisting of a specific pH or ionic strength required to provide a local chemical environment that is conducive to the activation, release, dissolution, or other improvement to the active payload, or to facilitate or enhance diffusion through the local tissue and microvasculature. It may also be an adjuvant that is more effective in the liquid form than in the solid form, thus allowing vaccines to be delivered with potentially attenuated dose sparing effect, whereby the adjuvant could act to provide enhanced immunogenicity, yet the vaccine stabilised by virtue of it being presented in a solid form rather than a liquid form, during storage. The liquid may be oil based or aqueous based and consist of one or more active agents or be completely inert. Under these circumstances the liquid is not required to be compatible with the microstructure carrier, as the duration of contact will be transient.

This embodiment of the invention may be achieved by have a multicompartment system, whereby at least one compartment contains a solid microstructure capable of penetrating the skin. This microstructure may or may not contain an active agent. This structure may be porous or contain cavities or a shape and geometry that allows a liquid payload to be loaded within it. At least one second compartment would exist in the vicinity of the first compartment containing a liquid payload. The two compartments would mix their contents prior to the insertion of the microstructure into the skin, the duration of mixing may be instant as the microstructure passes through the liquid containing compartment, or it may be stalled for a period of time sufficient to allow the liquid to be loaded into the microstructure after which the microstructure is inserted permanently or retractably into the skin.

One such method of achieving this is whereby a second compartment resides adjacent to the first compartment, directly below or tangential or sufficiently close whereby the microstructure passes through the substrate layer into the second compartment where it resides for a period of time or during its passage through the second compartment the microstructure is able to absorb or carry with it the liquid payload as it subsequently passes through the skin. An alternative method would be whereby a third compartment exists where the microstructure meets the contents of the second compartment, by breaking the seal or rupturing the barrier between the three compartments, the microstructure (carrier) compartment, the liquid compartment and the mixing compartment.

In this embodiment of the invention, it is possible therefore to have a carrier that is produced from materials described herein whereby the material would dissolve in the presence of a liquid medium. However, given the transient nature of the interaction between the liquid medium and the carrier, the carrier structural integrity and mechanical strength is retained for a sufficient period of time to enable the carrier to pass into the skin, where it eventually dissolves and is absorbed into the surrounding regions.

Each of the compartments may be produced from substrate materials previously described herein, and the compartments may be created using a layer-by-layer approach to create different compartments within different layers, or by using a single substrate whereby liquid is injected into a cavity within the substrate or injected into the substrate causing it to expand to accommodate the liquid.

is a schematic illustration of the carrier 3 containing voids 30 or cavities 31 that would be capable of carrying liquid from a peripheral source. The peripheral source may be a compartment or series of vesicles or pockets containing the liquid medium, which are ruptured as the carrier passes through them. The cavities may contain a material that is highly lipophilic such as lipids used in the preparation of liposomes, or surfactants with a high lipophilicity, or with a high aqueous affinity such as carbohydrates and sugars which rapidly and readily absorb aqueous based media. The lipophilic or hydrophilic material may also be nanosized particles or structures that coat the surface of the carrier such that they have a significantly increased surface area that leads to rapid absorption of the liquid medium. Such rapidly absorbing material would be preferably located sufficiently distanced from the leading tip of the carrier so as to retain structural and mechanical integrity of the carrier as it passes through the skin. A honeycomb-like structure for example could be created by 3D printing or using a mixture of a solid setting polymeric material in combination with a water-soluble excipient such as the sugars, and upon drying the carrier, the water soluble component may be washed out leaving behind a porous solid carrier matrix.

is a cross-section schematic illustrating the presence of a liquid reservoir 28. The reservoir 28 may be a compartment in its own right, embedded within the carrier substrate, or it may be an independent vesicle 29 or liquid carrier that is placed in a region adjacent to the region through which the carrier will pass. Examples of such carriers include soft gel capsules that are able to hold liquids for example, and thus a micro-scaled version of such capsules or indeed a sponge like material composed of cellulose or lipids holding the liquid. There may also be a spacer 32 between the carrier substrate layer and the liquid compartment substrate layer to prevent seepage of liquid in storage between the two layers. Additionally, the spacer may be movable so as to prevent accidental activation of the carriers prior to application of the patch to the skin, whereby the spacer is moved laterally enabling the carrier substrate layer and liquid compartment substrate layers to be able to abut or allow free movement of the carrier through the liquid compartment prior to passage into the skin.

is a cross-section schematic showing the removal of the spacer 32 between the carrier 3 substrate layer and the liquid compartment substrate layer containing a liquid compartment 28 or liquid vesicle 29. It will be appreciated to the person skilled in the art that there are several ways of configuring a spacer to ensure the upper and lower substrate sections are able to abut on removal of the spacer. The contact between the two layers is necessary to ensure the carrier 3 has a medium through which to pass through to retain its composure and orientation as it passes through the second compartment to allow the leading tip to penetrate the skin and pass through it. This may require one or more edges between the two layers to be sealed as the spacer 32 is withdrawn. The spacer may be produced from any of the aforementioned polymeric materials that confer the requisite mechanical integrity to fulfil its purpose as both a mechanical barrier and liquid tight seal between the two layers. It will equally be appreciated that a second spacer layer may be present between the liquid reservoir substrate layer and the skin, designed to limit the distance of travel of the carriers to enable sufficient time for the carriers to be loaded with the liquid, after which period the spacer may be removed to enable the auxiliary arms to push the carriers out of the substrate through the skin; this time may be controlled by the user, or mechanically controlled or digitally controlled using a time based indicator such as a flashing light emitting diode, vibration such as by using a piezo element, or audible alarm all linked to a switch that is activated when the first spacer is removed and/or the carriers are depressed and caused to move into the liquid compartment substrate layer, (and note these embodiments are not shown here as their integration into this system will be obvious to those skilled in the art). Furthermore, there may be more than one liquid reservoir layer and the patch/substrate may be adhered or anchored to the skin to prevent it moving as the spacer layers are withdrawn to enable successful penetration and passage of the carriers. The drug release kinetic may be modified through a combination of polymers and micro and/or nanoparticles, particle suspensions and liquid medium viscosity and density, to provide various types of drug release kinetics such as:

Zero-Order Kinetics

Constant Rate: Drug release occurs at a constant rate, independent of the concentration of the drug. This ensures a steady amount of drug is released over time.
Linear Release Profile: The cumulative amount of drug released versus time produces a straight line, indicating uniform release.
Ideal for Controlled Release: This kinetic model is ideal for maintaining consistent therapeutic drug levels in the body, often used in sustained-release formulations.

First-Order Kinetics

Concentration-Dependent: The rate of drug release is directly proportional to the concentration of the drug remaining in the dosage form.
Exponential Decay: The release rate decreases over time, resulting in a logarithmic decline in drug concentration.
Common in Immediate-Release Forms: This kinetic model is often observed in conventional dosage forms, such as tablets and capsules, where the drug is quickly released and absorbed.

Higuchi Model

Square Root of Time: Drug release is proportional to the square root of time, typically observed in systems where diffusion through a matrix is the controlling mechanism.
Porous Matrix: Often applies to matrix systems where the drug diffuses through a porous structure or a gel layer.
Useful for Semi-Solid Dosage Forms: Commonly used for transdermal systems, topical formulations, and some oral controlled-release systems where diffusion plays a key role.

Korsmeyer-Peppas Model

Empirical Model: This model describes drug release from polymeric systems using a simple power law expression, incorporating both diffusion and erosion mechanisms.
Mechanism Elucidation: The release exponent (n) helps identify the mechanism: Fickian diffusion (n ≤ 0.5), non-Fickian transport (0.5 < n < 1), and Case-II transport (n = 1).
Versatile Application: Applied to a variety of drug delivery systems including hydrogels, biodegradable polymers, and osmotic systems.

Hixson-Crowell Model

Geometric Changes: Assumes that the drug release is influenced by the change in surface area and diameter of the particles as they dissolve.
Cubic Root Kinetics: The rate of drug release is proportional to the cube root of the remaining drug mass, indicating uniform erosion or dissolution.
Application in Solid Dosages: Useful for predicting release profiles from dosage forms where the shape and size of the drug particles change over time, such as tablets and pellets.

Furthermore, the presence of liquid drug or drug in a medium where there is minimal or zero dissolution time required from the medium within which it is loaded, there could be an associated burst effect for the rapid of a dose of drug followed by one or more or combination of the above-mentioned drug release kinetics. This could in particular be beneficial for pain management for example, such as the opioid analgesics for breakthrough pain management or drugs for migraine where an initial rapid plasma drug concentration is required, followed by a constant rate of drug plasma level for example.

From the above description it will be apparent that the invention described has the following attributes :-

1. A carrier for the delivery of a therapeutic agent into the skin, comprising a solid, semi-solid, liquid, or combination thereof, designed to penetrate the skin and deliver the payload.

2. The carrier of attribute 1, wherein the carrier is in the form of a needle, star, cylindrical, conical, rectangular, or porous structure.

3. The carrier of attribute 1, wherein the carrier comprises a biodegradable, bioresorbable, or non-biodegradable material.

4. The carrier of attribute 1, wherein the payload is a drug, vaccine, cosmetic agent, vitamin, or mineral.

5. A substrate for holding the carrier, wherein the carrier is releasably or semi-permanently secured within the substrate for delivery of the payload.

6. The substrate of attribute 5, wherein the carrier is located within a cavity that allows for insertion of the carrier into the skin.

7. The carrier of attribute 1, wherein the sharpness of the carrier tip is designed to minimize insertion force and tissue penetration.

8. The carrier of attribute 1, wherein the carrier has a length to width ratio (aspect ratio) up to 10:1.

9. The carrier of attribute 1, wherein the carrier is capable of delivering multiple payloads simultaneously.

10. A method of delivering a therapeutic agent to the skin using the carrier of attribute 1, wherein the carrier is forced into the skin by an auxiliary arm.

11. The method of attribute 10, wherein the auxiliary arm is manually applied, mechanical such as spring-loaded, pneumatic, or mechanical roller.

12. The method of attribute 10, wherein the auxiliary arm exerts pressure sufficient to cause the carrier to penetrate the skin to a specified depth.

13. The method of attribute 10, wherein the insertion of the carrier into the skin results in the creation of microchannels that allow the payload to diffuse into the skin.

14. A patch or device comprising a carrier substrate and an auxiliary arm, wherein the auxiliary arm is used to insert the carrier into the skin.

15. The patch of attribute 14, wherein the carrier is embedded in a flexible, rigid, or semi-flexible material.

16. The patch of attribute 14, wherein the carrier substrate includes an adhesive for temporarily securing the patch to the skin during the insertion process.

17. The patch of attribute 14, wherein the auxiliary arm is actuated by a mechanical or pneumatic force to ensure the carrier is inserted into the skin.

18. The patch of attribute 14, wherein the carrier substrate and auxiliary arm are capable of providing feedback to the user that the carrier has been successfully delivered.

19. The patch of attribute 14, wherein the carrier is biodegradable, and no removal from the skin is required after delivery.

20. The patch of attribute 14, wherein the carrier substrate has a hollow or pre-cut section to facilitate the passage of the carrier through the skin.

21. A secondary carrier contained within the carrier substrate, wherein the secondary carrier delivers an agent separate from the primary payload.

22. The secondary carrier of attribute 21, wherein the secondary carrier is shaped as a sphere, cone, or cylinder or combination thereof.

23. The secondary carrier of attribute 21, wherein the secondary carrier is manufactured using moulding, embossing, 3D printing or similar techniques.

24. The secondary carrier of attribute 21, wherein the secondary carrier is used to deliver drugs, vaccines, or other therapeutics that may be incompatible with the primary carrier.

25. A method of using multiple carriers within a patch to deliver different payloads simultaneously or sequentially into the skin.

26. The method of attribute 25, wherein one carrier contains a drug and the other contains an adjuvant, or is constructed from an inert material for enhancing immune response through skin trauma.

27. The method of attribute 25, wherein the secondary carrier is used to deliver an agent that enhances the effectiveness of the primary payload.

28. A system for inserting the carrier into the skin comprising an auxiliary arm, a carrier substrate, and a feedback mechanism to confirm the delivery of the carrier to the skin.

29. The system of attribute 28, wherein the feedback mechanism comprises a locking mechanism that ensures the auxiliary arm has fully engaged with the carrier substrate.

30. The system of attribute 28, wherein the auxiliary arm is configured to provide pressure to the carrier without causing excessive force or skin damage.

31. A method of determining whether the full dose of the payload has been delivered using a locking or mating mechanism between the auxiliary arm and carrier substrate.

32. The method of attribute 31, wherein the user receives confirmation through tactile feedback, such as a click or resistance when the auxiliary arm is fully engaged.

33. A method of minimizing skin residence time for microneedle patches by optimizing carrier geometry, patch adhesion, or formulation for rapid drug delivery.

34. The method of attribute 33, wherein the carrier has rapid dissolution properties to reduce skin residence time.

35. The method of attribute 33, wherein the patch design minimizes skin irritation, discomfort, or damage during application.

36. A carrier substrate system with multiple carrier cavities designed to hold carriers for drug or vaccine delivery, wherein the cavities allow for precise insertion and drug release.

37. The carrier substrate system of attribute 36, wherein the carrier cavities are configured to accommodate a range of carrier shapes, sizes, or payloads.

38. The carrier of attribute 1, wherein the carrier is constructed from materials such as silicon, stainless steel, polymers, biodegradable materials, or ceramics.

39. The carrier of attribute 1, wherein the carrier is capable of providing controlled release or sustained release of the payload upon insertion into the skin.

40. The method of attribute 10, wherein the carrier is released after insertion into the skin, eliminating the need for further removal or mechanical force to extract it.

Further attributes of the invention are:

1. A device for delivering a therapeutic agent into the skin, comprising a payload carrier, and carrier substrate containing one or more carriers, wherein each carrier is releasably housed within the substrate.

2. The device of attribute 1, wherein the substrate material is further treated with chemical stabilizers, preservatives, or desiccants to prevent degradation of the active agent and preserve the sharpness of the carrier.

3. The device of attribute 1, wherein the substrate material includes one or more desiccant materials selected from activated alumina, silica gel, calcium chloride, magnesium sulfate, or any combination thereof, to prevent moisture absorption and protect the carrier's sharpness.

4. The device of attribute 1, wherein the substrate contains chemical stabilizers or preservatives such as cyclodextrins, chelating agents, benzalkonium chloride, or parabens to protect the active agent from degradation and prevent microbial growth.

5. A device comprising a removable carrier substrate, wherein the carrier is housed within the substrate material and is released when pressure is applied by an auxiliary arm.

a. The carrier substrate is composed of soft and pliable materials such as polyurethanes, silicones, or gels, allowing the carrier to pass through the substrate and penetrate the skin without significant deformation of the substrate.

b. The carrier substrate is configured with grooves, channels, or cavities to accommodate the carrier, and the carrier is forced out through the substrate by the auxiliary arm.

6. The device of attribute 5, wherein the auxiliary arm is configured to apply pressure to the carrier to ensure the carrier reaches the desired depth within the skin.

7. The device of attribute 5, wherein the substrate material allows for the carrier to be pushed through without flexing the substrate, ensuring efficient delivery of the payload.

8. The device of attribute 5, wherein the carrier substrate material is combined with stabilizers to prevent the active agent from degrading upon contact with the substrate, improving the overall stability and shelf-life of the device.

9. A device comprising a substrate and an auxiliary arm, wherein the auxiliary arm applies sufficient force to the carrier within the substrate to ensure it penetrates the skin with the required kinetic energy, while the substrate material allows for the smooth passage of the carrier.

10. The device of attribute 9, wherein the substrate has a thickness sufficient to allow momentum to build up before the carrier penetrates the skin, overcoming the skin resistance during the piercing process.

11. The device of attribute 9, wherein the substrate is designed to prevent the carrier from losing sharpness, and it includes desiccant materials such as silica gel or calcium chloride to protect the carrier during storage and before use.

12. A device comprising a substrate with one or more removable carrier anchors, wherein the anchor allows for the withdrawal of the carrier from the skin after it has been inserted, wherein the anchor is attached to the carrier by anchor arms that extend into the skin.

13. The device of attribute 12, wherein the carrier anchors rest on the surface of the skin, and the anchor arms reside primarily inside the skin, allowing the user to withdraw the carrier from the skin post-delivery.

14. The device of attribute 12, wherein the anchor arms are designed to pass through the substrate and rest on the skin surface, enabling the user to remove the carrier from the skin with minimal discomfort.

15. A device for the controlled removal of a carrier from the skin, comprising:

a. A substrate with carrier anchors attached to individual carriers, wherein the anchors allow the carrier to be withdrawn from the skin after the payload has been delivered.

b. The carrier anchors are accessible from the skin surface and are designed to withdraw the carrier by applying a force to the anchor arms.

16. The device of attribute 15, wherein the carrier anchors are designed to cut through the substrate, allowing them to pass through soft polymers or gels used in the substrate material, facilitating the removal process.

17. A device comprising a patch with one or more carriers housed in cavities within the substrate, wherein the patch is designed to be securely adhered to the skin during the insertion process, and the auxiliary arm is used to push the carriers through the skin, whereupon they are left in place.

18. The device of attribute 17, wherein the patch is removable after the carriers have been inserted, and the adhesive used ensures that the patch remains securely in place during application without causing discomfort.

19. A device comprising a substrate that contains an array of carriers, wherein the substrate material allows the carriers to pass through without deformation, and the substrate is designed to provide protection against environmental factors such as moisture, light, and heat.

20. The device of attribute 19, wherein the substrate is airtight, insulating, and opaque to protect the payload from light degradation and moisture exposure.

21. A device for delivering a therapeutic agent into the skin, wherein the carrier is composed of a material that can be released and withdrawn from the skin without requiring additional mechanical removal, and the carrier is housed within a flexible substrate that accommodates the carrier during delivery.

22. The device of attribute 21, wherein the carrier material is selected from biocompatible polymers, silicones, or gels, which provide a stable environment for the active agent and allow for precise delivery into the skin.

23. A device comprising a carrier constructed of a solid, semi-solid, liquid, or combination thereof, wherein the carrier is designed to penetrate the skin and deliver the payload.

24. The device of attribute 1, wherein the carrier is in the form of a needle, star, cylindrical, conical, rectangular, or porous structure.

25. The device of attribute 1, wherein the carrier is constructed from a biodegradable, bioresorbable, or non-biodegradable material.

26. The device of attribute 1, wherein the payload is a drug, vaccine, cosmetic agent, vitamin, or mineral.

27. A device comprising a carrier substrate designed to hold one or more carriers, wherein each carrier is releasably or semi-permanently secured within the substrate for delivery of the payload.

28. The device of attribute 5, wherein the substrate has cavities for housing the carriers, and the cavities allow for the insertion of the carrier into the skin.

29. The device of attribute 5, wherein the carrier substrate includes an adhesive for temporarily securing the patch to the skin during the insertion process.

30. The device of attribute 5, wherein the carrier substrate is made from a flexible, rigid, or semi-flexible material.

31. A device comprising an auxiliary arm configured to apply pressure to a carrier to force the carrier into the skin, wherein the auxiliary arm is actuated by a mechanical, pneumatic, or spring-loaded mechanism.

32. The device of attribute 9, wherein the auxiliary arm applies sufficient force to ensure the carrier penetrates the skin to a specified depth.

33. The device of attribute 9, wherein the auxiliary arm is configured to provide uniform pressure across multiple carriers to ensure consistent insertion into the skin.

34. The device of attribute 1, wherein the carrier is embedded within a flexible substrate, and the substrate is designed to conform to the skin surface for effective delivery of the payload.

35. A device comprising a feedback mechanism integrated into the carrier substrate and auxiliary arm, which provides tactile or visual confirmation that the carrier has been successfully delivered into the skin.

36. The device of attribute 13, wherein the feedback mechanism comprises a latching or locking mechanism that confirms the full insertion of the carrier into the skin.

37. A device comprising a secondary carrier embedded within a carrier substrate, wherein the secondary carrier holds a separate payload that is delivered into the skin along with the primary payload.

38. The device of attribute 15, wherein the secondary carrier is designed to increase the surface area for drug delivery and reduce the insertion force required to deliver the payload.

39. The device of attribute 15, wherein the secondary carrier is designed to improve the stability and shelf-life of the payload through encapsulation or protective coatings.

40. The device of attribute 1, wherein the carrier is equipped with a sharp tip designed to minimize insertion force and tissue damage during penetration into the skin.

41. The device of attribute 18, wherein the carrier has an aspect ratio (length to width ratio) of between 2:1 and 6:1, allowing for efficient skin penetration.

42. A device comprising a carrier substrate with multiple carrier cavities, each cavity designed to hold a carrier and deliver a therapeutic agent to the skin, wherein the cavities allow for the precise delivery of the agent.

43. The device of attribute 20, wherein the carrier cavities are configured to accommodate carriers of varying shapes and sizes to enable tailored drug delivery profiles.

44. A device comprising an auxiliary arm embedded within a carrier substrate, wherein the auxiliary arm is activated to push the carrier through the skin, providing efficient delivery of the therapeutic agent.

45. The device of attribute 22, wherein the auxiliary arm is attached to a spring-loaded, pneumatic, or motorized system to ensure consistent and controlled insertion of the carrier into the skin.

46. The device of attribute 22, wherein the carrier substrate is constructed from a rigid, compressible, or flexible material that allows the auxiliary arm to efficiently push the carrier through the skin without causing excessive force or discomfort.

47. A device comprising a carrier substrate and auxiliary arm configured to latch together, providing a visual or tactile indication that the carrier has been fully delivered into the skin.

48. The device of attribute 25, wherein the latch mechanism comprises latch points in the carrier substrate and an auxiliary pillar latch, which engages when the carrier is inserted to confirm full dose delivery.

49. A device comprising a patch where both the carrier substrate and auxiliary arm are integrated into a single unit, wherein the auxiliary arms are embedded in the patch material to allow for direct skin penetration upon pressing the patch onto the skin.

50. The device of attribute 27, wherein the single patch construct is airtight, light-blocking, and moisture-insulating to protect the payload and enhance product stability.

51. A device comprising a carrier anchor that allows the carrier to be withdrawn from the skin after the payload has been delivered, wherein the anchor is accessible from the skin surface.

52. The device of attribute 29, wherein the carrier anchor is attached to the carrier by anchor arms, and the anchor arms are configured to allow for withdrawal of the carrier from the skin.

53. The device of attribute 30, wherein the carrier anchor resides on the surface of the skin, while the anchor arms extend into the skin to facilitate the removal of the carrier.

54. A device comprising a secondary carrier system that allows for enhanced drug delivery, wherein the secondary carrier increases the drug payload capacity, improves drug stability, and reduces insertion force required to deliver the payload.

55. The device of attribute 32, wherein the secondary carrier is positioned adjacent to the primary carrier and is designed to facilitate efficient skin penetration and enhanced therapeutic efficacy.

56. The device of attribute 1, wherein the carrier is configured to be released after insertion into the skin, without the need for further mechanical removal or intervention.

57. A device comprising a micro-projection system that delivers individual microneedles or carriers into the skin of a subject with a precise mass and depth, wherein the device is designed for therapeutic or cosmetic purposes.

58. A device for delivering one or more additional carriers containing an active agent, wherein the carrier is designed to provide precise and controlled release upon insertion into the skin.

59. The device of attribute 36, wherein the auxiliary arm or auxiliary energy is used to apply pressure to the carrier and facilitate its delivery through the skin, ensuring consistent drug delivery.

60. A device comprising a carrier substrate with a series of grooves or channels in which the carriers are embedded, wherein the carriers can be forced out and into the skin by a mechanical force applied through the auxiliary arm.

61. The device of attribute 1, wherein the carrier is constructed to allow for sustained, controlled, or pulsatile release of the payload over a period of time, with release kinetics tailored to the needs of the therapeutic application.

62. A device for the delivery of a therapeutic agent, comprising a system that includes multiple carriers for the simultaneous or sequential delivery of various agents, wherein each carrier is independently controlled by an auxiliary arm or energy source to ensure precise and targeted drug delivery.

63. A device comprising a latching mechanism, wherein latch points are integrated into the carrier substrate, and an auxiliary pillar latch is incorporated to engage once the two patches are activated and mated together, providing confirmation that the carrier has been fully delivered into the skin.

64. The device of attribute 63, wherein the latching mechanism provides tactile or visual feedback to the user, ensuring that the full intended dose has been delivered.

65. A method for delivering a therapeutic agent into the skin, comprising the steps of using a patch system that integrates an auxiliary arm patch and a carrier substrate patch, wherein the patches engage through a latching mechanism to confirm the full delivery of the dose.

66. The method of attribute 65, wherein the latching mechanism provides confirmation that the carrier has been fully delivered, ensuring the patch may be disposed of once the dose is delivered.

67. A method for administering a single, integrated patch device, wherein the auxiliary arms are embedded within the patch, and the patch is pressed onto the skin, directly forcing the carriers through the skin to deliver the payload.

68. The method of attribute 67, wherein the integrated patch is airtight, insulating, and opaque to protect the encapsulated payload and enhance its stability.

69. A method for withdrawing a carrier from the skin, comprising the step of utilizing a carrier anchor that is accessible from the skin surface and attached to the carrier through anchor arms, allowing the user to pull and remove the carrier from the skin after the payload has been delivered.

Yet more attributes of the invention are:

1. A device for delivering a liquid or semisolid therapeutic agent into the skin, comprising a carrier substrate containing one or more carriers, wherein each carrier is releasably housed within the substrate, and the carrier is capable of holding a liquid or semisolid payload.

2. The device of attribute 1, wherein the liquid payload comprises an inert solution, a pro-drug, a pro-drug activator, or a medium consisting of specific pH or ionic strength to activate, release, dissolve, or facilitate the diffusion of the active agent through local tissue and microvasculature.

3. The device of attribute 1, wherein the liquid payload is selected from adjuvants, vaccines, pain management agents, or emergency medicines such as anti-snake venom, epinephrine, or naloxone, which require rapid absorption into the bloodstream.

4. The device of attribute 1, wherein the carrier is designed to carry liquid or semi-solid payloads, and the structural integrity of the carrier is retained during passage through the skin, with the payload being released into the surrounding tissues once the carrier reaches its intended location.

5. The device of attribute 1, wherein the carrier is made from a material that retains its mechanical strength for a sufficient period of time to enable skin penetration but dissolves or is absorbed after the liquid payload has been delivered.

6. The device of attribute 1, wherein the carrier includes a honeycomb-like structure, porous cavities, or cavities filled with lipophilic or hydrophilic material to enhance the absorption and retention of the liquid payload.

7. The device of attribute 1, wherein the liquid is an aqueous-based or oil-based medium, and the carrier's structure is adapted to retain the liquid payload until it is activated or mixed with the payload during its passage into the skin.

8. The device of attribute 1, wherein the liquid is mixed with an active agent within the carrier, such as a vaccine, or a therapeutic substance that becomes activated or releases upon insertion into the skin.

9. The device of attribute 1, wherein the carrier is housed in a multicompartment system, where at least one compartment contains a solid microstructure capable of penetrating the skin, and at least one second compartment contains a liquid payload.

10. The device of attribute 9, wherein the two compartments mix their contents prior to insertion of the microstructure into the skin, allowing the carrier to absorb or carry the liquid payload during its passage through the liquid compartment.

11. The device of attribute 9, wherein the microstructure (carrier) passes through the second compartment, mixing the liquid payload and solid agent during its passage, prior to insertion into the skin.

12. The device of attribute 9, wherein the second compartment is positioned adjacent to the first compartment, allowing the microstructure to absorb the liquid payload as it passes through the compartment during insertion.

13. The device of attribute 9, wherein the compartments are separated by a movable spacer, which prevents accidental activation of the carrier until the spacer is removed during application to the skin.

14. The device of attribute 9, wherein the spacer is produced from polymeric materials and serves as both a mechanical barrier and a liquid-tight seal between the compartments.

15. The device of attribute 9, wherein the spacer is removed before the carrier is inserted into the skin, and the liquid payload is delivered simultaneously with the active agent.

16. The device of attribute 1, wherein the liquid payload is contained in a reservoir or vesicle that is adjacent to the carrier, and the vesicle is ruptured during the insertion of the carrier to release the liquid into the skin.

17. The device of attribute 16, wherein the liquid reservoir is a soft gel capsule, sponge-like material composed of cellulose, lipids, or other liquid-holding materials that are capable of being ruptured upon the insertion of the carrier.

18. The device of attribute 16, wherein the liquid reservoir is embedded within the carrier substrate or placed in a region adjacent to the carrier, allowing the liquid to mix with the carrier as it passes through the device and into the skin.

19. The device of attribute 16, wherein the liquid is held within compartments in the carrier, and the carrier is designed to absorb or carry with it the liquid payload as it passes through the skin.

20. A method for delivering a liquid or semisolid therapeutic agent into the skin, comprising the steps of:

a. Inserting a carrier containing a liquid payload through the skin, wherein the carrier absorbs or carries the liquid during its passage into the skin.

b. The liquid payload is selected from inert solutions, pro-drugs, pro-drug activators, adjuvants, or any other substance that is activated or absorbed upon contact with the skin.

c. The liquid payload is delivered to the interstitial space or microvasculature upon penetration of the carrier, where it is rapidly absorbed.

21. The method of attribute 20, wherein the carrier is a porous or honeycomb-like structure that holds the liquid payload and allows for the controlled release of the payload as the carrier passes through the skin.

22. The method of attribute 20, wherein the liquid payload is mixed with the solid carrier upon passage through a compartment containing the liquid, and the contents are combined before reaching the skin.

23. The method of attribute 20, wherein the liquid payload is activated by specific pH or ionic conditions upon reaching the skin, allowing for controlled release and absorption of the active agent.

24. The method of attribute 20, wherein the liquid payload is released through the skin simultaneously with the insertion of the microstructure, where it is rapidly absorbed into the bloodstream or microvasculature.

25. A method for activating and delivering a liquid payload into the skin, comprising:

a. Inserting a carrier that holds a liquid payload using an auxiliary arm, wherein the carrier is configured to absorb or carry the liquid during its passage through the skin.

b. The carrier is configured with a porous or cavity-filled structure that holds the liquid and allows it to mix with the active agent during the insertion process.

c. The liquid payload is then released and absorbed into the skin, delivering the therapeutic agent to the interstitial space or microvasculature.

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 skilled person 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 that claim or the invention, or causing a so-called intermediate generalisation.

Claims

A device for delivering one or more agents into the skin of a patient, the device comprising one or more agent carriers each associated with a carrier supporting substrate, wherein the or each carrier is releasable from the substrate and wherein the or each carrier is capable of penetrating said skin to administer the agent into the skin.
A device as claimed in claim 1, further including an administering arm associated with the or each carrier, the or each arm being moveable relative to the substrate and capable of causing said penetration of the carrier into the skin in use, wherein the substrate holds the or each carrier and the or each respective administering arm, and wherein the respective arm is in register with a respective carrier.
A device as claimed in claim 2, including a mechanical latching arrangement between the substrate and the dispensing arm operable when the arm is sufficiently extended from the substrate to complete said penetration.
A device as claimed in claim 3, wherein the latching arrangement provides force feedback to confirm delivery of the agent.
A device as claimed in claim 2,3 or 4, wherein force for said penetration is provided by manual, spring load, pneumatic or roller means acting on the or each arm.
A device as claimed in claim 5, wherein the force is controlled or controllable to provide a predetermined penetration depth.
A device as claimed in any one of claims 2 to 6 wherein the arm provides visual confirmation of said penetration.
A device as claimed in any one of the preceding claims wherein the or each carrier has sufficient mechanical strength to pierce the skin and, is porous or dissolvable to deliver said agent(s).
A device as claimed in any one of the preceding claims, wherein the or each carrier has a honeycomb-like structure, porous cavities, or cavities filled with lipophilic or hydrophilic material to enhance the absorption and retention of the agent during manufacture or storage, and/or wherein the or each carrier is formed from, or includes a biodegradable, bioresorbable, or non-biodegradable material or a combination of those materials, and /or the or each carrier holds or is formed substantially from the agent, and/or wherein the or each carrier is in the form of solid, semi-solid, a liquid or a combination thereof, and/or wherein the material of the or each carrier is selected from biocompatible polymers, silicones, or gels, and/or wherein the or each carrier is in the form of needle, star cylindrical, conical, rectangular, or porous structure, and/or wherein the or each carrier includes one or more cavities where the or each agent is stored separately for delivering one agent or more than one agent simultaneously, and/or wherein the or each carrier has a sharp tip arranged to minimize insertion force and skin tissue penetration, and/or wherein the carrier is embedded in a flexible, rigid or semi-flexible material , and/or wherein the or each carrier has a length to width ratio (aspect ratio) of 10:1 or less, for example 9:1 and preferably a ratio between about 2:1 and 6:1 for example about4:1.
A device as claimed in any one of the preceding claims, wherein the substrate includes an adhesive coated face for temporarily securing the device to the skin during delivery of the agent(s), and/or the substrate includes apertures or pre-cut regions to facilitate the passage of a respective carrier through the substrate, and/or wherein the substrate is treated with chemical stabilizers, preservatives, such as cyclodextrins, chelating agents, benzalkonium chloride, or parabens , or desiccants to prevent degradation of the or each agent and preserve the sharpness of the or each carrier, and/or the substrate includes one or more desiccant materials selected from activated alumina, silica gel, calcium chloride, magnesium sulphate, or any combination thereof, to prevent moisture absorption and protect the carrier's (s’) sharpness, and/or wherein the substrate is formed from resilient or compliant material such as polyurethanes, silicones, or gels, for allowing the or each carrier to pass therethrough without significant deformation or flexing of the substrate, and/or wherein the substrate is configured with grooves, channels, or cavities to accommodate the or each carrier, and/or wherein the substrate has a thickness sufficient to allow a suitable momentum of the carrier to be achieved prior to its penetration into the skin, and/or wherein the substrate is hermetic, heat insulating, and opaque to light, to protect the agent(s) from light degradation and moisture exposure.
A device as claimed in any one of the preceding claims, wherein said agent(s) is or are primary agents and the substrate, holds a secondary carrier separate from the carrier, the secondary carrier comprising a secondary agent or agents.
A device as claimed in claim 11 wherein the secondary carrier is spherical, conical, cylindrical or combination thereof, and/or is operable to deliver said secondary agent(s) which is/are incompatible in storage with said primary agent(s).
A device as claimed in any one of the preceding claims further including an anchor or tether connected to the or each carrier, allowing for the removal of the or each carrier by means of pulling a respective anchor or tether.
A device as claimed in claim 13, wherein the or each anchor or tether is attached to the or a substrate.
A method for delivering an agent, for example a therapeutic or cosmetic agent, into the skin of a patient, the method comprising the steps of providing a device as claimed in any one of the preceding claims, forcing the or each carrier of said device into the skin of the patient, and removing the substrate of said device to leave only the or each carrier in the skin.
A method as claimed in claim 15, wherein a dispensing arm is used to force the or each carrier into the skin to a predetermined depth.
A method as claimed in claim 15 or 16, wherein said carrier(s) include tethers external to the skin after insertion and the or each carrier is removed from the skin after delivery of the agent by means of pulling on the or each tether.
A device or method as claimed in any preceding claims, wherein the or each agent is a drug, vaccine, cosmetic agent, vitamin, mineral or combination thereof, and/or the or each agent comprises or is comprised of an inert solution, a pro-drug, a pro-drug activator, or a medium consisting of specific pH or ionic strength to activate, release, dissolve, or facilitate the diffusion of the active agent through local tissue and microvasculature and/or the or each agent is selected from adjuvants, vaccines, pain management agents, or emergency medicines such as anti-snake venom, epinephrine, or naloxone, for rapid absorption into the bloodstream, .
A device or method as claimed in any preceding claims, wherein a first component of the or each agent includes is an aqueous-based or oil-based liquid, and is allowed to mix with a second component of the agent in use of the device.
A device or method as claimed in any one of the preceding claims, wherein the second component is activated by the first component.