GB2621527A

GB2621527A - Microneedle patch

Info

Publication number: GB2621527A
Application number: GB2318051.6A
Authority: GB
Inventors: Bartenev Ian
Original assignee: Microneedle Solutions Ltd
Current assignee: Microneedle Solutions Ltd
Priority date: 2022-05-10
Filing date: 2022-05-10
Publication date: 2024-02-14
Also published as: GB202318051D0

Abstract

The method comprises the steps of forming a first base 4a having a plurality of cylinders arranged in an array; applying a droplet comprising a vaccine to each of the plurality of cylinders; forming a second base 4b, identical to the first base, having a second plurality of cylinders arranged in an array; superimposing the first and second bases so as to adhere the droplets between opposing cylinders forming a microneedle patch precursor 10; cooling the microneedle patch precursor; and increasing the distance between the first and second bases so as to elongate and separate the droplets into microneedles 12 forming two microneedle patches.

Description

MICRONEEDLE PATCH

FIELD OF THE INVENTION

The invention relates to a microneedle patch, and associated method of manufacture, in particular to a microneedle patch suitable for the delivery of a vaccine to a user.

BACKGROUND TO THE INVENTION

Vaccination can provide safe and effective immune preparation against a variety of different viruses. However, the typical mechanism of vaccine delivery is an injection which many people do not like as it causes pain and tissue damage. In addition, in order to receive the vaccine, people need to go to a hospital or visit a doctor's surgery where a trained professional will inject the vaccine. Therefore, the process of being vaccinated can be painful, takes a lot of time and is often stressful to users who are needle-phobic.

The stratum corneum constitutes the main barrier of the epidermis to exogenous substances, including small and high weight molecular bio-polymers compositions used as cosmetic fillers. Techniques aimed at removing the stratum corneum barrier, such as tape-stripping and suction, laser, or thermal ablation are impractical, while needle-free injections have so far failed to replace known needle-based delivery. Such a method of delivery can be uncomfortable, and even painful, due to the shape of the needles and the viscosity of the composition, and are thus non-attractive for the users.

The solution to this is to promote self-administrative microneedle patches. According to news and many articles, there has been a lot of research and development made to move this idea to the market but ordinary people still do not know about this option and the technology is still relatively new and untested.

The production of solid microneedles arrays has been described in the art. For example, W02009/040548A1 discloses a micro-protrusion array for use in transport of a material across a biological barrier, wherein said array comprises a plurality of micro-protusions composed of a swellable polymer composition. US2015/0141910 discloses systems and methods relating to microneedles, including a first element including an array of micro-projections and a second element including a supportive substrate upon which the micro-projections are formed perpendicular to the substrate surface. W02016/076442 discloses a microneedle comprising a plurality of portions, wherein the plurality of portions comprise a distal end portion and a proximal end portion, at least two of the plurality of portions are made of different polymers, and the distal end portion is made of at least one polymer with high swellability and high viscoelasticity.

Therefore, microneedles have an advantage of potentially penetrating the stratum corneum, without the discomfort of known needles, and can be self-administered. Microneedle patches suitable for the delivery of cosmetics are known. For example, "Droplet-born air blowing: Novel dissolving microneedle fabrication" to Kim, J.D. eta/in Journal of Controlled Release (2013), Vol.170, No.3, pp.430-436 discloses a microneedle-mediated drug delivery system which has been developed to provide painless self-administration of drugs in a patient-friendly manner. Kim also discloses a displacement-force test machine and method for use, so as to determine the force required of microneedles in order to penetrate the skin. This has been calculated to be 0.058 N. "Pharmaceutical assessment of polyvinylpyrrolidone (PVP): As excipient from conventional to controlled delivery systems with a spotlight on COVID-19 inhibition." to Kurakula, M. eta/in Journal of Drug Delivery Science and Technology (2020), No. 60, p.102046 discloses polyvinylpyrrolidone (PVP) is a water-soluble polymer obtained by polymerization of monomer N-vinylpyrrolidone. PVP is an inert, non-toxic, temperature-resistant, pH-stable, biocompafible, biodegradable polymer that helps to encapsulate and cater both hydrophilic and lipophilic drugs. These advantages enable PVP as a versatile excipient in the formulation development of broad conventional to novel controlled delivery systems. "Dissolving Microneedle Patches for Dermal Vaccination." to Leone, M. eta/in Pharmaceutical Research (2017), Vol.34, No.11, pp.2223-2240 discloses the dermal route is an attractive route for vaccine delivery due to the easy skin accessibility and a dense network of immune cells in the skin. The development of microneedles is crucial to take advantage of the skin immunization and simultaneously to overcome problems related to vaccination by conventional needles (e.g pain, needle-stick injuries or needle re-use). "Minimally Invasive Protein Delivery with Rapidly Dissolving Polymer Microneedles." to Sullivan, S.P. et a/ in Advanced Materials (2008), Vol.20, No.5, pp.933-938 discloses rapidly dissolving polymer needles of micron dimensions for the painless, self-administered delivery of biomolecules. The drug is encapsulated within these polymer microneedles, and after insertion into the skin, the biocompatible polymer dissolves within minutes to release the encapsulated cargo and leave behind no biohazardous sharps or need for removal.

During the manufacturing of cosmetic patches, the physical process conditions often exceed temperatures higher than 8 °C, or alternatively UV light is often used. It is known that vaccines degrade fast when the temperature exceeds 8 °C, or when UV light is present.

Therefore, modifying existing cosmetic patches to deliver vaccines to a user would result in ineffective vaccine patches. A further reason why existing cosmetic patches cannot just be modified into microneedle patches for the delivery of vaccines is because the microneedles are made of different chemicals and are manufactured in different ways.

There is therefore a need to overcome the problems stated in the prior art. In particular to develop a microneedle patch suitable for the delivery of a vaccine to a user which has improved microneedles that can effectively deliver a therapeutic agent into the desired target anatomical location.

SUMMARY OF THE INVENTION

The invention is set out in accordance with the appended claims. The present invention provides for a method of forming at least one microneedle patch suitable for administering a vaccine to an individual, the method comprising the steps of: a) forming a first base having a plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the first base; b) applying a droplet comprising a vaccine to each of the plurality of cylinders of the first base; c) forming a second base having a second plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the second base; d) superimposing the first and second bases so as to adhere the droplets between opposing cylinders; and e) increasing the distance between the first and second bases so as to elongate and separate the droplets into microneedles forming two microneedle patches.

The method of the invention allows for the production of at least two microneedle patches, wherein the microneedles of the respective patches are formed from a solution containing the vaccine of interest to be administered. In essence, the novel method transforms a vaccine solution into a series of microneedles for the delivery of the vaccine across the stratum corneum. This allows for the vaccine to be delivered to antigen-presenting cells (APC's) such as Langerhans cells or dermal dendritic cells. APC's incorporating the vaccine then travel to lymph nodes where Ag-specific T-cells and B-cells activate forming an immune response.

Preferably, the first and second bases are formed by fused deposition modelling (FDM), stereolithography (SLA) or digital light processing (DLP) 3D printing. Fused deposition modelling, or FDM 3D Printing, is a method of additive manufacturing where layers of materials are fused together in a pattern to create an object. The material is usually melted just past its glass transition temperature, and then extruded in a pattern next to or on top of previous extrusions, creating an object layer by layer. In layman's terms, a typical FDM 3D printer takes a plastic filament and squeezes it through a hot end, melting it and then depositing it in layers on the print bed. These layers are fused together, building up throughout the print, and eventually they will form the finished part. Many types of materials can be used with FDM techniques, including the most common thermoplastics, chocolate, pastes, and even "exotic" materials like metal-or wood-infused thermoplastic. Widely accepted as the simplest way to achieve 3D printing, FDM is cheap and fairly efficient. FDM 3D printers dominate the 3D printing market, almost drowning out more expensive methods.

Stereolithography belongs to a family of additive manufacturing technologies known as vat photopolymerization, commonly known as resin 3D printing. These machines are all built around the same principle, using a light source, a laser or projector, to cure liquid resin into hardened plastic. The main physical differentiation lies in the arrangement of the core components, such as the light source, the build platform, and the resin tank. SLA 3D printers use light-reactive thermoset materials called "resin". When SLA resins are exposed to certain wavelengths of light, short molecular chains join together, polymerizing monomers and oligomers into solidified rigid or flexible geometries. SLA parts have the highest resolution and accuracy, the sharpest details, and the smoothest surface finishes of all 3D printing technologies, but the main benefit of the stereolithography lies in its versatility. Material manufacturers have created innovative SLA resin formulations with a wide range of optical, mechanical, and thermal properties to match those of standard, engineering, and industrial thermoplastics. SLA 3D printers start to work by lowering the build platform into the resin-filled tank with only one layer of height left between the bottom of the tank and the build platform. Then the galvanometers take over. Galvanometers are mirror-like components used for navigating the laser beam of an SLA printer to the bottom of the tank. With the help of G-code, galvanometers navigate the laser beam in a path which represents one layer of a certain part. The laser then cures the resin making a solid layer of a part. When one layer is complete, the build platform moves up by one layer in height and the process is repeated until the part is complete.

DLP is a "sister technology" to SLA as the only big difference is the light source used to cure the resin. SLA printers use lasers combined with galvanometers to cure resin. With a DLP 3D printer, the light source is a specially developed digital light projector screen. With this screen, DLP is generally considered to be faster than SLA. With SLA, the laser has to individually cure the resin in a "point to point" technique. On the other hand, a DLP projector screen flashes an image of a layer all at once. Thus, all points of a layer can be cured simultaneously. In this way, the print speed is increased in comparison to SLA since it takes less time to cure a single layer. Since the DLP is a digital technology, the 20 image that is projected is composed of pixels. When translated into three dimensions, they become voxels. The light source of a DLP 3D printer itself, an LED screen, means nothing without a digital micromirror device (DMD), the "heart' of every DLP chipset. A DMD contains hundreds of thousands or even millions of small micromirrors that direct the light and create the pattern of a layer onto the bottom of the resin tank. The resolution of a printed part using a DLP 3D printer usually corresponds to the number of micromirrors inside a DMD device.

Preferably, the first and second bases are formed from a source of polyethylene terephthalate glycol thermoplastic polyester. Polyethylene terephthalate glycol thermoplastic polyester is ideally suited to 3D-printing techniques as it can easily be moulded into a variety of forms. Preferably, the first and second bases are formed from a source of biocompatible resin. Biocompatible reins have a higher hydrophilic activity which reduces the possibility that the microneedles disconnect from the bases when the first and second bases are formed from a plastic polymeric material.

Preferably, the first and second bases are formed as a continuous strip or roll. Continuous 3D-printing of a strip or roll of material is more efficient and cost-effective than producing individual microneedle patch bases.

Preferably, the first and second bases are cut into discrete microneedle patch bases. This allows individual microneedle patch bases to be cut to the required dimensions for a user.

Preferably, the first and second bases are identical. This allows them to be superimposed on top of each other so as to form a microneedle patch precursor. If the bases are of differing dimensions, preferably the configuration of the plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the first and second bases is identical such that the plurality of cylinders are superimposable mirror images of each other. This ensures that when a droplet of the vaccine solution is applied to each of the plurality of cylinders on the first base, the plurality of cylinders on the first base can be lined up with the corresponding plurality of cylinders on the second base, such that the respective droplets are adhered between each opposing plurality of cylinders.

Preferably, prior to the addition of the droplet of vaccine to the plurality of cylinders of the first base, the entire first base is sprayed with a hydrophobic spray to ensure that the surface of the first base is hydrophobic. This boosts droplet elongation. Preferably, the entire second base is also sprayed with a hydrophobic spray to ensure that the surface of the second base is hydrophobic prior to the step of droplet adhesion when the first and second bases are superimposed on top of each other.

Preferably, in step b) each droplet comprises at least 0.25 pL, preferably at least 0.3 pL, preferably at least 0.35 pL, preferably at least 0.4 pL, preferably at least 0.45 pL, preferably at least 0.5 pL, preferably at least 0.55 pL, preferably at least 0.6 pL, preferably at least 0.65 pL, preferably at least 0.7 pL, preferably at least 0.75 pL, preferably at least 0.8 pL, preferably at least 0.85 pL, preferably at least 0.9 pL, preferably at least 0.95 pL or preferably at least 1 pL. Preferably, in step b) each droplet comprises at most 0.75 pL, preferably at most 0.8 pL, preferably at most 0.85 pL, preferably at most 0.9 pL, preferably at most 0.95 pL, preferably at most 1 pL, preferably at most 1.05 pL, preferably at most 1.1 pL, preferably at most 1.15 pL, preferably at most 1.2 pL, preferably at most 1.25 pL, preferably at most 1.3 pL, preferably at most 1.35 pL, preferably at most 1.4 pL, preferably at most 1.45 pL or preferably at most 1.5 1.1. Preferably, in step b) each droplet comprises between 0.5 pL and 1 pL. A droplet having a volume in this range incorporates the necessary quantity of vaccine and additional materials which is required to be delivered to a user.

Preferably, in step b) each droplet comprises vaccine present in an amount of at least 0.1 pL, preferably at least 0.125 pL, preferably at least 0.15 pL, preferably at least 0.175 pL, preferably at least 0.2 pL, preferably at least 0.225 pL, preferably at least 0.25 pL, preferably at least 0.275 pL or preferably at least 0.3 pL. Preferably, in step b) each droplet comprises vaccine present in an amount of at most 0.2 pL, preferably at most 0.225 pL, preferably at most 0.25 pL, preferably at most 0.275 pL, preferably at most 0.3 pL, preferably at most 0.325 pL, preferably at most 0.35 pL, preferably at most 0.375 pL or preferably at most 0.4 pL. Preferably, in step b) each droplet comprises vaccine present in an amount of between 0.125 pL and 0.25 pL. This provides for an effective amount of vaccine to be delivered to a user.

Preferably, in step b) each droplet comprises vaccine present in a concentration of at least 10% w/v, preferably at least 15% w/v, preferably at least 20% w/v, preferably at least 25% w/v, preferably at least 30% w/v, preferably at least 35% w/v, preferably at least 40% w/v, preferably at least 45% w/v or preferably at least 50% w/v. Preferably, in step b) each droplet comprises vaccine present in a concentration of at most 20% w/v, preferably at most 25% w/v, preferably at most 30% w/v, preferably at most 35% w/v, preferably at most 40% w/v, preferably at most 45% w/v, preferably at most 50% w/v, preferably at most 55% w/v, preferably at most 60% w/v, preferably at most 65% w/v or preferably at most 70% w/v. Preferably, in step b) each droplet comprises vaccine present in a concentration in a range of from 25% w/v to 50 % w/v. Preferably, in step b) each droplet comprises vaccine present in a concentration of at least 25% w/v. This provides for an effective amount of vaccine to be delivered to a user.

Preferably, in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration of at least 10% w/v, preferably at least 15% w/v, preferably at least 20% w/v, preferably at least 25% w/v, preferably at least 30% w/v, preferably at least 35% w/v, preferably at least 40% w/v, preferably at least 45% w/v, preferably at least 50% w/v, preferably at least 55% w/v, preferably at least 60% w/v, preferably at least 65% w/v, preferably at least 70% w/v, preferably at least 75% w/v, preferably at least 80% w/v. Preferably, in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration of at most 20% w/v, preferably at most 25% w/v, preferably at most 30% w/v, preferably at most 35% w/v, preferably at most 40% w/v, preferably at most 45% w/v, preferably at most 50% w/v, preferably at most 55% w/v, preferably at most 60% w/v, preferably at most 65% w/v, preferably at most 70% w/v, preferably at most 75% w/v or preferably at most 80% w/v. Preferably, in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration in a range of from 25% w/v to 50% w/v. Preferably, in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration of at least 50% w/v. The addition of polyvinylpyrrolidone increases the elasticity of the vaccine matrix solution. As a result, when droplets of the vaccine matrix solution are applied to each of the cylinders it is easier for the droplets to deform when the first and second bases are moved towards or away from each other. In this way, it is easier for microneedles to form when the first and second surfaces are moved apart.

Preferably, in step b) the droplet further comprises a biocompatible dye. Microneedles, due to their size, tend to be difficult to observe. Having a biocompabble dye incorporated into the matrix solution ensures that they can be seen easily on the microneedle patch prior to use, and their absence after afterwards indicates successful application of the vaccine across the stratum corneum.

After the two bases have been superimposed onto each other with droplets of vaccine on each of the cylinders of the first base adhering to the corresponding cylinders on the second base to form the microneedle patch precursor, the steps of holding the two bases at a set distance from each other, cooling the microneedle patch precursor and slowly increasing the distance of the two bases from one another ensures that the drops of vaccine are slowly transformed into microneedles. These stages of elongation and solidification of the vaccine microneedles ensures that microneedles are produced to a high degree of accuracy such that they are suitable for vaccine administration. The skilled person will be aware that the stages of elongation and solidification of the vaccine microneedles can be performed when the first and second bases are horizontal to each other, or alternatively when the first and second bases are vertical to each other. When the first and second bases are arranged horizontal to each other then, due to the force of gravity, microneedles formed on the second base will be longer than those formed on the first base. Microneedle patches with longer microneedles are suitable for administering vaccines to adults, whereas microneedle patches with shorter microneedles are suitable for administering vaccines to children and the elderly because their skin is typically thinner. When the first and second bases are arranged vertically to each other, microneedles formed on both the first and second bases will be identical in size and length to each other.

Preferably, the superimposing step comprises holding the first surfaces of the first and second bases at a distance of at least 1.5 mm from each other for a period of at least 10 minutes. This is good because if the distance is increased too much, the droplet can divide and disconnect between the first and second bases. If the distance is increased too little, the droplets of vaccine tend to form the wrong shape making it more difficult for the microneedles to administer the vaccine droplets.

Preferably, in step f) the distance between the first surfaces of the first and second bases is increased to 2 mm for a period of at least 5 minutes. This is good because, again, if the distance is increased too much, the droplet can divide and disconnect between the first and second bases. If the distance is increased too little, the droplets of vaccine tend to form the wrong shape making it more difficult for the microneedles to administer the vaccine droplets Preferably, in step f) the first and second bases are separated from each other at a rate of 0.1 mm/min. This is good because if the rate is much higher, the distance between first and second bases is increased too much, and the vaccine droplets can divide and disconnect between the first and second bases. If the rate is much lower such that the distance between first and second bases is increased too little, the droplets of vaccine tend to form the wrong shape leading to harder microneedles separation.

Preferably, in step f) the first and second bases are separated from each other by a linear actuator. This ensures that a distance between the first and second bases can be easily controlled with a high degree of accuracy and precision.

Preferably, the linear actuator comprises a screw and a stepper motor. This ensures that a distance between the first and second bases can be easily and smoothly controlled to prevent the microneedles from rupturing prior to their construction.

Preferably, the cooling step comprises placing the microneedle patch precursor in a refrigerator at a temperature of at least 0 °C, preferably at least 1 °C, preferably at least 2 °C, preferably at least 3 °C, preferably at least 4 °C, preferably at least 4 °C, preferably at least 5 °C or preferably at least 6 °C. Preferably, the cooling step comprises placing the microneedle patch precursor in a refrigerator at a temperature of at most 10 °C, preferably at most 9 °C, preferably at most 8 °C, preferably at most 7 °C, preferably at most 6 °C or preferably at most 5 %. Preferably, the cooling step comprises placing the microneedle patch precursor in a refrigerator at a humidity of at least 35 %, preferably at least 40 %, preferably at least 45 %, preferably at least 50 %, preferably at least 55 %, preferably at least 60 %, preferably at least 65 % or preferably at least 70 %. Preferably, the cooling step comprises placing the microneedle patch precursor in a refrigerator at a humidity of at most 70 %, preferably at most 65 %, preferably at most 60 %, preferably at most 55 %, preferably at most 50 % or preferably at most 45 %. Preferably, the cooling step comprises placing the microneedle patch precursor in a refrigerator at a temperature of between 2 °C and 8 °C and a humidity of less than 65%. This allows a variety of vaccine microneedle patches to be produced which do not require specialist temperature storage conditions (La below freezing) in order to maintain the viability of the vaccine during storage prior to use. Preferably, a dehumidifier can also be used to decrease the humidity within the refrigerator. Preferably, such vaccines are selected from, but not limited to, AZD1222 or Spikevax.

Preferably, the cooling step further comprises placing the microneedle patch precursor in a freezer at a temperature of at least -110 °C, preferably at least -100 °C, preferably at least -90 °C, preferably at least -80 °C, preferably at least -70 °C, preferably at least -60 °C or preferably at least -50 °C. Preferably, the cooling step further comprises placing the microneedle patch precursor in a freezer at a temperature of at most -60 °C, preferably at most -55 °C, preferably at most -50 °C, preferably at most -45 °C, preferably at most -40 °C, preferably at most -35 °C, preferably at most -30 °C or preferably at most -25 °C.

Preferably, the cooling step further comprises placing the microneedle patch precursor in a freezer at a pressure of less than 3 Pa, preferably less than 4 Pa, preferably less than 5 Pa, preferably less than 6 Pa, preferably less than preferably less than 7 Pa, preferably less than 8 Pa, preferably less than 9 Pa, preferably less than 10 Pa, preferably less than 11 Pa or preferably less than 12 Pa. Preferably, the cooling step further comprises placing the microneedle patch precursor in a freezer for a period of at most 5 hours, preferably at most 6 hours, preferably at most 7 hours, preferably at most 8 hours, preferably at most 9 hours, preferably at most 10 hours, preferably at most 11 hours, preferably at most 12 hours, preferably at most 13 hours, preferably at most 14 hours or preferably at most 15 hours. Preferably, the cooling step further comprises placing the microneedle patch precursor in a freezer at a temperature of between -55 °C and -99 °C and at a pressure of less than 10 Pa for a period of at most 12 hours. This additional step increases the shelf-life of vaccine microneedle patches produced in this manner, and is most suitable for producing microneedle patches where the temperature of the vaccine must be kept below freezing. For this additional step, preferably the vaccine is selected from, but not limited to, BNT162b2. Microneedle patches produced in this way have the additional advantage of having a high porosity due to sublimation of any water present during the freeze-drying step.

Preferably, microneedles formed according to the method all have the same dimensions. That is to say, microneedles formed according to the method have the same length. In order to ensure this, preferably, during the separation step, a polymer laser cutter can be employed to ensure that the microneedles on the first and second bases are all of the same length. This provides for uniform-sized microneedles on both the first and second bases.

Methods of measuring temperature, humidity and pressure are well known to the skilled person and as such, further specific details are not included at this time. The skilled person is however referred to the details and methods disclosed in ISO 8187:1991 (Household refrigerating appliances -Refrigerator-freezers -Characteristics and test methods), ISO 4677-1:1985 (Atmospheres for conditioning and testing -Determination of relative humidity -Part 1: Aspirated psychrometer method) and ISO 5160-1:1979 (Commercial refrigerated cabinets -Technical specifications -Part 1: General requirements) as a starting point for any assistance.

The invention also provides for a microneedle patch formed according to any of the methods as herein described.

The invention also provides for a kit comprising a microneedle patch formed according to any of the methods as herein described and an applicator. The kit can then be developed as a single-use, or multi-use kit, (as required) for a user of vaccines.

Preferably the applicator comprises a housing for the microneedle patch per se or for a microneedle patch formed according to the method as previously described. The housing preferably has a button for displacing the microneedle patch from the housing and a protective adhesive tape layer for applying the applicator to the skin of a user. The housing ensures that the microneedles are maintained at an appropriate humidity level so as to increase the shelf life of the vaccine. In use the applicator is placed onto the skin of a user and the button is depressed so that the microneedle patch is displaced from the housing. The microneedles pierce the protective adhesive layer and the vaccine is delivered to the skin of the user.

A further aspect of the invention relates to a microneedle patch, comprising a base having a plurality of cylinders arranged in an array and extending perpendicularly away from a first surface of the base, the cylinders being coated with a matrix solution comprising a vaccine so as to define a series of microneedles. A microneedle patch having a plurality of cylinders coated with a matrix solution comprising a vaccine so as to define a series of microneedles is good because each of the microneedles are formed from the vaccine to be administered. This promotes self-administration of vaccines and avoids using traditional needles to inject a vaccine into a user which can be stressful, painful, time consuming, or a combination of all three.

Preferably, the base is formed from a source of polyethylene terephthalate glycol thermoplastic polyester. Polyethylene terephthalate glycol thermoplastic polyester is ideally suited to 3D-printing techniques as it can easily be moulded into a variety of forms. While it is envisaged that a microneedle patch according to the invention will have a square or rectangular base configuration, the skilled person will appreciate that other shapes are equally anticipated, such as for example a circular microneedle patch. A circular microneedle patch has the advantage that an equal force is distributed over each of the plurality of microneedles when the microneedle patch is applied to a user's skin.

Preferably, the base is formed by fused deposition modelling (FDM), stereolithography (SLA) or digital light processing (DLP) 3D printing. The advantages of the different methods of 3D-printing have been previously discussed, and apply mutatis mutandis on this occasion.

Preferably, the base is formed as a continuous strip or roll. Continuous 3D-printing of a strip or roll of material is more efficient and cost-effective than producing individual microneedle patch bases.

Preferably, the base is cut into discrete microneedle patch bases. This allows individual microneedle patch bases to be cut to the required dimensions for a user.

Preferably, the thickness of the base is at least 0.5 mm, preferably at least 0.55 mm, preferably at least 0.6 mm, preferably at least 0.65 mm, preferably at least 0.7 mm, preferably at least 0.75 mm, preferably at least 0.8 mm, preferably at least 0.85 mm, preferably at least 0.9 mm, preferably at least 0.95 mm or preferably at most 1.0 mm. Preferably, the thickness of the base is at most 1.2 mm, preferably at most 1.15 mm, preferably at most 1.1 mm, preferably at most 1.05 mm, preferably at most 1.0 mm, preferably at most 0.95 mm, preferably at most 0.9 mm, preferably at most 0.85 mm, preferably at most 0.8 mm, preferably at most 0.75 mm, preferably at most 0.7 mm or preferably at most 0.65 mm. Preferably, the thickness of the base is in the range 0.6 mm to 0.8 mm. Preferably, the thickness of the base is 0.75 mm. This is good because this ensures that a relatively small microneedle patch can be produced which has sufficient strength to be able to deliver vaccine droplets via the plurality of microneedles.

Preferably, the overall dimensions of the sides of the base are at least 1.5 cm, preferably at least 1.6 cm, preferably at least 1.7 cm, preferably at least 1.8 cm, preferably at least 1.9 cm, preferably at least 2.0 cm, preferably at least 2.1 cm, preferably at least 2.2 cm, preferably at least 2.3 cm, preferably at least 2.4 cm, preferably at least 2.5 cm, preferably at least 2.6 cm, preferably at least 2.7 cm, preferably at least 2.8 cm, preferably at least 2.9 cm or preferably at least 3.0 cm. Preferably, the overall dimensions of the sides of the base are at most 3.5 cm, preferably at most 3.4 cm, preferably at most 3.3 cm, preferably at most 3.2 cm, preferably at most 3.1 cm, preferably at most 3.0 cm, preferably at most 2.9 cm, preferably at most 2.8 cm, preferably at most 2.7 cm, preferably at most 2.6 cm, preferably at most 2.5 cm, preferably at most 2.4 cm, preferably at most 2.3 cm, preferably at most 2.2 cm, preferably at most 2.1 cm or preferably at most 2.0 cm. Preferably, the base has overall dimensions of 2.5 x 2.5 cm. This is good because it ensures that a sufficient number of microneedles containing the vaccine can be allocated to a single microneedle patch.

Preferably, the number of the plurality of cylinders is at least 60, preferably at least 65, preferably at least 70, preferably at least 75, preferably at least 80, preferably at least 85, preferably at least 90, preferably at least 95, preferably at least 100, preferably at least 105, preferably at least 110, preferably at least 115 preferably at least 120, preferably at least 125, preferably at least 130, preferably at least 135, preferably at least 140, preferably at least 145 or preferably at least 150. Preferably, the number of the plurality of cylinders is at most 180, preferably at most 175, preferably at most 170, preferably at most 165, preferably at most 160, preferably at most 155, preferably at most 150, preferably at most 145, preferably at most 140, preferably at most 135, preferably at most 130, preferably at most 125, preferably at most 120, preferably at most 115, preferably at most 110, preferably at most 105 or preferably at most 100. Preferably, the number of the plurality of cylinders is in the range 75 to 125. Preferably, the number of the plurality of cylinders is 100. This is good because it ensures that there are a sufficient number of microneedles on the microneedle patch to be able to deliver enough vaccine to a user in order to produce an efficient immune response.

Preferably, the plurality of cylinders is arranged in an array such that the number of cylinders arranged along the x-axis of the array is at least 6 cylinders, preferably at least 7 cylinders, preferably at least 8 cylinders, preferably at least 9 cylinders, preferably at least 10 cylinders, preferably at least 11 cylinders, preferably at least 12 cylinders, preferably at least 13 cylinders, preferably at least 14 cylinders, preferably at least 15 cylinders, preferably at least 16 cylinders, preferably at least 17 cylinders, preferably at least 18 cylinders, preferably at least 19 cylinders or preferably at least 20 cylinders. Preferably, the plurality of cylinders is arranged in an array such that the number of cylinders arranged along the y-axis of the array is at least 6 cylinders, preferably at least 7 cylinders, preferably at least 8 cylinders, preferably at least 9 cylinders, preferably at least 10 cylinders, preferably at least 11 cylinders, preferably at least 12 cylinders, preferably at least 13 cylinders, preferably at least 14 cylinders, preferably at least 15 cylinders, preferably at least 16 cylinders, preferably at least 17 cylinders, preferably at least 18 cylinders, preferably at least 19 cylinders or preferably at least 20 cylinders. Preferably, the plurality of cylinders is arranged in a 10 x 10 array. This is good because it ensures that there are sufficient numbers of microneedles on the microneedle patch for delivery of vaccine in the limited space available.

Preferably, the height of the plurality of cylinders is at least 0.4 mm, preferably at least 0.45 mm, 0.5 mm, preferably at least 0.55 mm, preferably at least 0.6 mm, preferably at least 0.65 mm, preferably at least 0.7 mm, preferably at least 0.75 mm, preferably at least 0.8 mm, preferably at least 0.85 mm, preferably at least 0.9 mm, preferably at least 0.95 mm or preferably at most 1.0 mm. Preferably, the height of the plurality of cylinders is at most 1.2 mm, preferably at most 1.15 mm, preferably at most 1.1 mm, preferably at most 1.05 mm, preferably at most 1.0 mm, preferably at most 0.95 mm, preferably at most 0.9 mm, preferably at most 0.85 mm, preferably at most 0.8 mm, preferably at most 0.75 mm, preferably at most 0.7 mm, preferably at most 0.65 mm, preferably at most 0.6 mm or preferably at most 0.55 mm. Preferably, the height of the plurality of cylinders is in the range 0.4 mm to 0.8 mm. Preferably, the height of the plurality of cylinders is 0.6 mm. This is good because cylinders help to deliver the upper part of the microneedle to the exact portion of the stratum corneum layer where vaccines can be absorbed most effectively. This avoids vaccine wastage.

Preferably, the distance between each of the plurality of cylinders is at least 1.4 mm, preferably at least 1.45 mm, preferably at least 1.5 mm, preferably at least 1.55 mm, preferably at least 1.6 mm, preferably at least 1.65 mm, preferably at least 1.7 mm, preferably at least 1.75 mm, preferably at least 1.8 mm, preferably at least 1.85 mm, preferably at least 1.9 mm, preferably at least 1.95 mm or preferably at least 2.0 mm. Preferably, the distance between each of the plurality of cylinders is at most 2.2 mm, preferably at most 2.15 mm, preferably at most 2.1 mm, preferably at most 2.05 mm, preferably at most 2.0 mm, preferably at most 1.95 mm, preferably at most 1.9 mm, preferably at most 1.85 mm, preferably at most 1.8 mm, preferably at most 1.75 mm, preferably at most 1.7 mm, preferably at most 1.65 mm, preferably at most 1.6 mm or preferably at most 1.55 mm. Preferably the distance between each of the plurality of cylinders is in the range 1.4 mm to 2.0 mm. Preferably, the distance between each of the plurality of cylinders is at least 1.5 mm. A minimum distance between adjacent microneedles is required in order to ensure that no additional force is required by a user when applying the microneedle patch to their skin in order for the microneedles penetrate the upper layers of stratum corneum. A distance of less than 1.5 mm between adjacent microneedles requires additional force which can lead to the microneedles rupturing before they have been inserted into a user's skin.

Preferably, alternate rows of the plurality of cylinders in the array are offset from each other. This is good because it increases the application of vaccine across a user's skin.

Preferably, the matrix solution further comprises polyvinylpyrrolidone dissolved in water in an amount of greater than 50% w/v. This is good because the addition of polyvinylpyrrolidone increases the elasticity of the matrix solution. As a result, when droplets of the matrix solution are applied to each of the cylinders it is easier for the droplets to deform when the first and second bases are moved towards or away from each other. In this way, it is easier for microneedles to form when the first and second surfaces are moved apart.

Preferably, the vaccine is present in the matrix solution in a concentration of at least 25% w/v. This provides for an effective amount of vaccine to be delivered to a user.

Preferably, the matrix solution comprises a biocompatible dye. Microneedles, due to their size, tend to be difficult to observe. Having a biocompatible dye incorporated into the matrix solution ensures that they can be seen easily on the microneedle patch prior to use, and their absence after afterwards indicates successful application of the vaccine to the user's skin.

The invention also provides for a kit comprising the microneedle patch according to the further aspect of the invention and an applicator, as previously discussed.

BRIEF DESCRIPTION OF THE DRAWINGS

The description is given with reference to the accompanying drawings where like numerals are intended to refer to like parts as follows: 2 microneedle patch 4a first base 4b second base 6a plurality of cylinders on first base 6b plurality of cylinders on second base 8 first surface of the base microneedle patch precursor 12 microneedles 14 applicator and in which: Figure 1 shows a view in cross-section of a microneedle patch of the invention; Figure 2 shows a close-up view of Figure 1; and Figures 3a to 3d show a schematic view of the steps of forming a microneedle patch according to the method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Figure 1 shows a view in cross-section of a microneedle patch 2 according to the invention. The microneedle patch 2 has a base 4a with a plurality of cylinders 6a arranged in an array and extending perpendicularly away from a first surface 8 of the base 4a. The base 4a is formed from polyethylene terephthalate glycol thermoplastic polyester and is formed by a fused deposition modelling 3D-printing process. Figure 1 shows that the base 4a of the microneedle patch 2 is a square, although the skilled person will appreciate that other shapes are equally anticipated. The dimensions of the base 4a are approximately 2.5 x 2.5 cm, with a depth of 0.75 mm.

The plurality of cylinders 6a is arranged in rows and Figure 1 illustrates that the plurality of cylinders 6a is formed into a 9 x 10 array. Again, the skilled person will appreciate that different numbers for the plurality of cylinders 6a in the array, and indeed the configuration of the plurality of cylinders 6a in the array, are equally anticipated. The height of each of the plurality of cylinders 6a is 0.6 mm, and the distance between each of the plurality of cylinders 6a is at least 1.5 mm.

The plurality of cylinders 6a is coated with a matrix solution comprising a vaccine so as to define a corresponding series of microneedles 12. The matrix solution further comprises polyvinylpyrrolidone dissolved in water in an amount of at least 50% w/v. The vaccine is present in the matrix solution in a concentration of at least 25% w/v. The matrix solution also comprises a biocompatible dye.

For ease of reference, Figure 2 shows a close-up view of the microneedle patch of Figure 1.

Figures 3a to 3d show a schematic view of the steps involved of forming a microneedle patch 2 according to the method of the invention. Figure 3a shows a first base 4a having a plurality of cylinders 6a arranged in an array and extending perpendicularly away from a first surface 8 of the first base 4a. A droplet comprising a vaccine is shown applied to each of the plurality of cylinders 6a of the first base 4a. Each droplet comprises between 0.5 pL and 1 p, and each droplet comprises vaccine present in an amount of between 0.125 pL and 0.25 1.1. Each of the droplets further comprises a biocompatible dye.

Figure 3b shows the first base of Figure 3a along with a second base 4b, identical to the first base 4a, having a second plurality of cylinders 6b arranged in an array and extending perpendicularly away from a first surface 8 of the second base 4b. The first 4a and second 4b bases are formed by fused deposition modelling (FDM), stereolithography (SLA) or digital light processing (DLP) 3D printing, and the first 4a and second 4b bases are formed from polyethylene terephthalate glycol thermoplastic polyester. The first 4a and second 4b bases are superimposed on top of each other so as to adhere the droplets between opposing cylinders 6a, 6b so as to define a microneedle patch precursor 10. The superimposing step comprises holding the first surfaces 8 of the first 4a and second 4b bases at a distance of at least 1.5 mm from each other for a period of at least 3 hours.

Figure 3c shows that the distance between the first 4a and second bases 4b is increased so as to elongate and separate the droplets into microneedles 12 forming two microneedle patches 2. The distance between the first surfaces 8 of the first 4a and second 4b bases is increased to 2 mm for a period of at least 5 minutes. This process is conducted while the microneedle patch precursor 10 is cooled to the requisite temperature, via simple refrigeration or by placing the microneedle patch precursor 10 in a freezer, depending on the composition of the vaccine that has been applied to the plurality of cylinders 6a of the first base 4a. If the vaccine is suitable for chilling by way of refrigeration, the cooling step comprises placing the microneedle patch precursor 10 in a refrigerator at a temperature of between 2°C and 8°C and a humidity of less than 65%. If the vaccine is suitable for chilling by way of freezing, the cooling step further comprises placing the microneedle patch precursor 10 in a freezer at a temperature of between -55 °C and -99 °C and at a pressure of less than 10 Pa for a period of at most 12 hours. The process is also carried out such that the first 4a and second 4b bases are separated from each other at a rate of 0.1 mm/min.

Finally, Figure 3d shows the complete separation of the microneedle patch precursor 10 into two separate microneedle patch bases 2, each having been formed with a plurality of microneedles 12 extending from the surface of the corresponding plurality of cylinders 6a, 6b on each of the first 4a and second 4b bases.

The following numbered sentences are within the scope of the present invention.

1. A method of forming at least one microneedle patch 2 suitable for administering a vaccine to an individual, the method comprising the steps of: a) forming a first base 4a having a plurality of cylinders 6a arranged in an array and extending perpendicularly away from a first surface 8 of the first base 4a; b) applying a droplet comprising a vaccine to each of the plurality of cylinders 6a of the first base 4a; c) forming a second base 4b having a second plurality of cylinders 6b arranged in an array and extending perpendicularly away from a first surface 8 of the second base 4b; d) superimposing the first 4a and second 4b bases so as to adhere the droplets between opposing cylinders 6a, 6b so as to define a microneedle patch precursor 10; e) cooling the microneedle patch precursor 10; and f) increasing the distance between the first 4a and second 4b bases so as to elongate and separate the droplets into microneedles 12 forming two microneedle patches 2.

2. The method according to 1, wherein the first 4a and second 4b bases are formed by fused deposition modelling (FDM), stereolithography (SLA) or digital light processing (DLP) 3D printing.

3. The method according to 1 or 2, wherein the first 4a and second 4b bases are formed from polyethylene terephthalate glycol thermoplastic polyester.

4. The method according to 3, wherein first 4a and second 4b bases are formed as a continuous strip or a roll.

5. The method according to 4, wherein the first 4a and second 4b bases are cut into discrete microneedle patch bases.

6. The method according to any preceding sentence, wherein the first 4a and second 4b bases are identical.

7. The method according to any preceding sentence, wherein in step b) each droplet comprises between 0.5 pL and 1 pL.

8. The method according to any preceding sentence, wherein in step b) each droplet comprises vaccine present in an amount of between 0.125 pL and 0.25 pL.

9. The method according to any preceding sentence, wherein in step b) each droplet comprises vaccine present in a concentration of at least 25% w/v.

10. The method according to any preceding sentence, wherein in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration of at least 50% w/v.

11. The method according to any preceding sentence, wherein in step b) the droplet further comprises a biocompatible dye.

12. The method according to any preceding sentence, wherein the superimposing step comprises holding the first surfaces 8 of the first 4a and second 4b bases at a distance of at least 1.5 mm from each other for a period of at least 10 minutes.

13. The method according to any preceding sentence, wherein in step f) the distance between the first surfaces 8 of the first 4a and second 4b bases is increased to 2 mm for a period of at least 5 minutes.

14. The method according to any preceding sentence, wherein in step f) the first 4a and second 4b bases are separated from each other at a rate of 0.1 mm/min.

15. The method according to any preceding sentence, wherein in step f) the first 4a and second 4b bases are separated from each other by a linear actuator.

16. The method according to 15, wherein the linear actuator comprises a screw and a stepper motor.

17. The method according to any preceding sentence, wherein the cooling step comprises placing the microneedle patch precursor 10 in a refrigerator at a temperature of between 2°C and 8°C and a humidity of less than 65%.

18. The method according to any preceding sentence, wherein the cooling step further comprises placing the microneedle patch precursor 10 in a freezer at a temperature of between -55 °C and -99 °C and at a pressure of less than 10 Pa for a period of at most 12 hours.

19. The method according to any of 1 to 17, wherein the vaccine is selected from AZD1222 or Spikevax.

20. The method according to 18, wherein the vaccine is selected from BNT162b2.

21. A microneedle patch 2 formed according to the method of any preceding claim.

22. A kit comprising the microneedle patch 2 according to 21 and an applicator 14.

Claims

CLAIMS: 1. A method of forming at least one microneedle patch 2 suitable for administering a vaccine to an individual, the method comprising the steps of: a) forming a first base 4a having a plurality of cylinders 6a arranged in an array and extending perpendicularly away from a first surface 8 of the first base 4a; b) applying a droplet comprising a vaccine to each of the plurality of cylinders 6a of the first base 4a; c) forming a second base 4b having a second plurality of cylinders 6b arranged in an array and extending perpendicularly away from a first surface 8 of the second base 4b; d) superimposing the first 4a and second 4b bases so as to adhere the droplets between opposing cylinders 6a, 6b so as to define a microneedle patch precursor 10; e) cooling the microneedle patch precursor 10; and f) increasing the distance between the first 4a and second 4b bases so as to elongate and separate the droplets into microneedles 12 forming two microneedle patches 2, wherein the first 4a and second 4b bases are identical.
2. The method according to claim 1, wherein the first 4a and second 4b bases are formed by fused deposition modelling (FDM), stereolithography (SLA) or digital light processing (DLP) 3D printing.
3. The method according to claim 1 or claim 2, wherein the first 4a and second 4b bases are formed from polyethylene terephthalate glycol thermoplastic polyester.
4. The method according to any preceding claim, wherein in step b) each droplet comprises between 0.5 pL and 1 pL.
5. The method according to any preceding claim, wherein in step b) each droplet comprises vaccine present in an amount of between 0.125 pL and 0.25 pL.
6. The method according to any preceding claim, wherein in step b) each droplet comprises vaccine present in a concentration of at least 25% w/v.
7. The method according to any preceding claim, wherein in step b) the vaccine is mixed with polyvinylpyrrolidone dissolved in water in a concentration of at least 50% w/v.
8. The method according to any preceding claim, wherein in step b) the droplet further comprises a biocompatible dye.
9. The method according to any preceding claim, wherein the superimposing step comprises holding the first surfaces 8 of the first 4a and second 4b bases at a distance of at least 1.5 mm from each other for a period of at least 10 minutes.
10. The method according to any preceding claim, wherein in step f) the distance between the first surfaces 8 of the first 4a and second 4b bases is increased to 2 mm for a period of at least 5 minutes.
11. The method according to any preceding claim, wherein in step f) the first 4a and second 4b bases are separated from each other at a rate of 0.1 mm/min.
12. The method according to any preceding claim, wherein in step f) the first 4a and second 4b bases are separated from each other by a linear actuator.
13. The method according to claim 12, wherein the linear actuator comprises a screw and a stepper motor.
14. The method according to any preceding claim, wherein the cooling step comprises placing the microneedle patch precursor 10 in a refrigerator at a temperature of between 2°C and 8°C and a humidity of less than 65%.
15. The method according to any preceding claim, wherein the cooling step further comprises placing the microneedle patch precursor 10 in a freezer at a temperature of between -55 °C and -99 °C and at a pressure of less than 10 Pa for a period of at most 12 hours.
16. The method according to any of claim 1 to claim 14, wherein the vaccine is selected from AZD1222 or Spikevax.
17. The method according to claim 15, wherein the vaccine is BNT162b2.