Patent Application
20230270985
The invention concerns a device for introducing microneedles into the skin of a subject; and a method for inserting microneedles into the skin of a subject comprising use of said device.
Biopharmaceuticals are delivered predominantly using hypodermic needles, with over 16 billion injections given worldwide each year. However, injections using hypodermic needles are not generally well-accepted by patients due to pain, bleeding, fear of needles, and the need for administration by skilled healthcare workers. As an alternative, microneedles (MNs) have been investigated for a diversity of medical applications, especially where the delivery of bioactives to the skin is the primary focus.
MNs are micron-sized, needle-like projections, often organized in an array having a defined geometric pattern on a planar base plate and, amongst other applications, are currently being exploited for the targeted intraepidermal and intradermal delivery of drugs and vaccines. Due to their microscopic dimensions MNs do not penetrate skin deep enough to cause any significant pain, bleeding or scarring, as demonstrated through numerous clinical trials. The application of MNs to the skin surface results in penetration of the outer skin barrier, the stratum corneum (SC) without impinging significantly on nerves or blood vessels. Most notably, the micron-scale dimensions of the MNs allow for their simple and direct application into skin without requiring professional training, and therefore they avoid the shortcomings of conventional hypodermic needles.
MN fabrication has dramatically grown over the past 15 years. This technology has enabled a variety of different MNs to be made for drug delivery to the skin and other targets. MNs have been fabricated out of many different materials including silicon, metals, polymers, and ceramics using a variety of different fabrication methods including lithography, wet and dry etching, laser cutting and micro-moulding. This has led to various types of MNs being developed, mainly: (i) solid microneedles for skin pre-treatment to increase skin permeability, (ii) microneedles coated with drug that dissolves and run off in the skin, (iii) dissolving polymer microneedles that contain drug and both the microneedle and the drug fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin.
Dissolving or degrading MNs are commonly made of a biodegradable polymer that contains pharmaceuticals within a polymer matrix, wherein the pharmaceutical is released after skin insertion/embedding via dissolving or degradation of the polymeric matrix. Dissolving or degrading MNs have received attention as an innovative transdermal drug delivery system due to minimum pain on delivery, biocompatibility and patient convenience. However, in spite of these advantages, some challenges for the complete delivery of such pharmaceuticals exist because of the incomplete or irreproducible insertion of the dissolvable MNs. For example, due to the viscoelastic properties of the skin, dissolvable MNs may lack the requisite rigidity, compared to their solid material counterparts, to completely penetrate the skin surface and so often fail. Further, even if capable of penetrating the skin, often the complete delivery of the pharmaceutical agent is not achieved.
The successful use of MNs often depends on the function of the device used for MN insertion into the skin, skin recovery, and drug stability during manufacture, storage and delivery, and also on patient outcomes, including lack of pain, skin irritation and skin infection. Usually, dissolvable or degradable MNs are fabricated on an adhesive patch that facilitates their insertion into the skin and aims to keep them on or in the skin until they are completely dissolved, however, this arrangement can be associated with allergic responses and has been reported to be uncomfortable. Further, the patch must be in intimate contact with the skin for the time necessary to deliver the pharmaceutical agent which, in the case of long-term agent delivery, can be problematical. Additionally, in situations requiring long-term agent delivery, it is essential that the microneedles are fully inserted and firmly embedded into the skin in order to ensure correct dosing.
Consequently, we herein describe a novel device for the simple introduction and embedding/implantation of microneedles into the skin for use, for example, in intradermal drug delivery and with particular application in the context of long-term agent delivery. Notably, the device is configured to prevent exposure of microneedles during transport and storage, and to control the force of insertion of the microneedles into the skin. Further, and importantly, the device is also configured so that insertion and detachment of the microneedles, and so proper embedding in the skin, is easily achieved, this allows for consistent and reproducible implantation of MNs, which ensures reliable delivery of agents, such as therapeutics and pharmaceuticals, at the correct dosage and for prolonged periods of time.
According to a first aspect of the invention there is provided a device [1] for introducing/embedding microneedles into the skin of a subject said device comprising:
is moveably mounted in a first housing [2a] to move with respect to said housing [2a] from a retracted to an extended position where, when in said extended position, said microneedles or part thereof [4] project beyond said housing [2a] and further wherein said at least one carrier
is also moveably mounted in said housing [2a] to move with respect to said housing [2a] laterally or at 90° with respect to said movement that produces the afore extension;
In a preferred embodiment of the invention said carrier [3] is mounted on or in a plate [7] or between a pair of plates [7]. Plate(s) [7] is/are, ideally, adapted to engage a movable support [8] that can move with respect to said first housing [2a] from a retracted to an extended position where, when in said extended position, said microneedles [4] or part thereof project beyond said first housing [2a] and further wherein said carrier [3] or plate [7] is also moveably mounted in said first housing [2a] to move with respect to said first housing [2a] laterally, or at 90° with respect to said movement that produces the afore extension. In an alternative embodiment of the invention, said carrier [3] is mounted directly on said movable support [8] which performs the afore functions.
Most preferably a plurality of said carriers [3] are provided and each is, ideally, mounted on one, or between a pair, of said plates [7]. More ideally still a plurality of said plates [7] are mounted on said movable support [8] in an aligned manner. More ideally still movement of said movable support [8] brings about synchronised and ideally coordinated movement of said plates [7] whereby said plates [7] move together from a retracted to an extended position, either simultaneously or in a synchronised fashion. In an alternative embodiment of the invention, said carrier [3] is mounted directly on said movable support [8] which performs the afore functions.
In a further preferred embodiment, a plurality of said movable supports [8] are provided, each carrying a plurality of said plates [7] whereby a number of plates [7] are housed within said first housing [2a], ideally, to form at least one array [9]. In an alternative embodiment of the invention, a plurality of said carriers [3] are mounted directly on said movable supports [8] whereby a number of said carriers are housed within said first housing [2a], ideally to form at least one array [9].
More ideally still said first [2a] and second housings [5a] are movably engaged there together whereby they can move with respect to each other.
Preferably said at least one actuator [6] is a fixed part of said second housing [5a] but able to move with respect to said first housing [2a] by way of movement of said first [2a] and second housings [5a] with respect to each other, ideally manually operated movement.
More preferably still, said plurality of carriers [3] or plates [7] are mounted on said movable support [8] and, under the influence of said actuator (6), said support [8], by way of a downward stroke, moves said carriers [3] or plates [7] from a retracted to an extended position where, when is said extended position, said MNs [4] or part thereof project beyond said first housing [2a].
Yet more preferably, said plurality of carriers [3] or plates [7] are mounted on said movable support [8] to slide laterally whereby once, under the influence of said actuator [6], said support [8], by way of a downward stroke, moves said carriers [3] or plates [7] from a retracted to an extended position, when in said extended position, the continued downward stroke of said actuator [6] is translated into a lateral force as a result of a stopping member [10] preventing further downward motion, this lateral force then forces said carriers [3] or plates [7] there apart whereby said carriers [3] or plates [7] move laterally, and ideally, a number of carriers [3] or plates [7] move laterally in a first direction and another number move laterally in a second opposite direction, with respect to said first direction. Most preferably about an equal number of carriers [3] or plates [7] move in said lateral first and second directions.
Yet more preferably still, at least one of said housings [2a, 5a] comprises an indicator [11] which indicates when the extended/downward and/or lateral movement is complete. Preferably, said indicator [11] is a marker that becomes visible, or sits in a more visible position, once said afore movement(s) is/are complete to indicate that said microneedles [4] have penetrated and/or been left in the skin.
In a yet further preferred embodiment of the invention said actuator [6] makes contact with said movable support [8] and by doing so moves said carriers [3] or plates [7] mounted on same. Preferably a number of carriers [3] or plates [7] are provided each one mounted on the same or different movable supports [8].
Reference herein to a microneedle(s) [4] refers to at least one microneedle, ideally a plurality, wherein said microneedle(s) have the requisite length, diameter and physical arrangement necessary for insertion into the skin. In a preferred embodiment, the microneedle(s) have a length of from about 10 μm to about 1500 μm. More preferably, the microneedle(s) have a length of from about 50 μm to about 1000 μm.
More preferably still, said microneedle(s) comprise a point of weakness to facilitate breakage such as, but not limited to, a taper and further include a neck region [4a] or indented region which forms a point of weakness for the breakage of same upon lateral movement and so helps with detachment of said MNs from the carrier so that the MNs, or at least their tips, are deployed within the skin. In this embodiment, it advantageously has been found that the detached microneedles exhibit improved anchorage in the skin thus facilitating skin embedding/insertion. Preferably, said points of weakness are manufactured towards or at the base of the, or each, microneedle such that the majority of said microneedles are delivered into the skin.
Preferably said microneedles [4] are circular or semi-circular in cross section and when the latter they are selectively aligned so that, in use, their curved surface faces towards the downward stroke of the actuator [6] and their flat surface away from the downward stroke of said actuator [6], or vice versa.
In a further preferred embodiment, said microneedles [4] are dissolvable or degradable or substantially dissolvable or degradable microneedles. Dissolvable or degradable microneedles are known in the art and refer to those microneedles that are manufactured from a solid, or substantially solid, material but wherein said solid material has the ability to pass or reduce into the surrounding environment under certain conditions, such as when in contact with an aqueous environment or the skin. Ideally the microneedles are made from a polymer which can be bio-absorbable or biodegradable. In a preferred embodiment, said dissolvable microneedles may be manufactured from materials of synthetic or natural origin. Non-limiting examples of suitable materials include: vinyl polymers such as polyvinyl alcohol (PVA), polyvinyl chloride, polyvinyl fluoride, polystyrenes, poly(vinyl imidazole) and polymers of ethylene-vinyl acetates; polyacrylates; polyurethanes; polyesters such as poly(valeric acid), poly butyric acid, poly lactides (PLA), polyglycolides (PGA), poly (lactide-co-glycolide) (PLGA), poly caprolactone (PCL), poly butylene succinate (PBS), poly p-dioxanone (PPDO), and aromatic co-polyesters; polyethylene oxide; chlorosulphonate polyolefins; polyanhydrides; polyorthoesters; polysaccharides such as acyl substituted cellulose acetates; polycarbonates; polyamides and poly ester-amides. Mixtures and/or copolymers of the above materials may also be used.
In a preferred embodiment, said dissolvable or degradable microneedles [4] and said carrier [3] are manufactured from the same material.
Alternatively, said dissolvable or degradable microneedles [4] and said carrier [3] are manufactured from different materials, for example where the cost of agent to be delivered is substantial, the microneedles are made from a material that contains or is impregnated with said agent and the carrier is made from any suitable material known in the art that can function as a support or substrate for the microneedles such as, but not limited to, metals, ceramics, organics, polymers or composites or the like, so minimizing material/agent waste. Further, as will be appreciated, through use of different polymers for the microneedle and the carrier, differential mechanical properties can be achieved thus facilitating MN detachment from the carrier.
Alternatively, said microneedles are not necessarily dissolvable or degradable and so are coated with a delivery agent.
Accordingly, in a preferred embodiment of the invention, said microneedles [4] comprise at least one therapeutic, pharmaceutical, cosmetic or biological agent for delivery into the skin. Said agent(s) include(s) active agents intended for topical, local, and/or systemic delivery. Generally, any drug or active agent can be delivered using the microneedles of the present invention, specifically those that are known to be effective when delivered via the skin. Preferably, said agent includes any conventional medicament, therapeutic, contraceptive or cosmetic agent, vaccine, protein, antibody, or structural agent.
In a preferred embodiment said microneedles [4] are either hollow or solid. When the microneedles are hollow, said agent(s) is/are ideally loaded into the hollow portion of the MNs and delivered to the subject on insertion of the MNs into the skin and/or as the MNs dissolve. When the MNs are solid, said agent(s) is/are loaded in the material of the MNs, and delivered to the subject on insertion of the MNs into the skin and/or as the MNs dissolve.
Depending upon the agent(s) to be delivered, as well as the desired length of time of delivery, and the polymer used to form the MNs, the MNs can be configured to dissolve at a predetermined rate to thus release said agent(s) at a predetermined rate when embedded in the skin.
Thus, MNs [4] which are detached from the device and left embedded in the skin can provide for sustained or extended release of agent(s) delivered by the MNs [4].
In a preferred embodiment, said microneedles are configured for rapid release of said agent(s) and thus they are made from a material that rapidly dissolves in the skin. Alternatively, said microneedles are configured for prolonged and sustained release of said agent(s) and thus they are made from a material that slowly dissolves in the skin. Reference herein to rapidly dissolving MNs is to needles that delivers their agent(s) within minutes, hours or a day of insertion and reference herein to slowly dissolving MNs is reference to needles that delivers their agent(s) within days or months or years of insertion.
In a particularly preferred embodiment of the invention, said first [2a] and second housings [5a] are movably engaged there together whereby they can move with respect to each other and said actuator [6] is a fixed part of said second housing [5a]. In use, such a device [1] is placed against a site where microneedles are to be embedded/inserted and movement of said second housing [5a], by the depression of same, generates a downward stroke which, via said actuator [6], moves said carriers [3] or plates [7] mounted on said movable support [8], to an extended position whereby said microneedles or parts thereof [4] project beyond said first housing [2a] (into skin). Moreover, continued downward movement of said second housing [5a] is translated, by a stopping member [10] that prevents further downward movement, into a lateral force that slides said carriers [3] or plates [7] laterally along the movable support [8], resulting in a shearing force being exerted on said microneedles [4] which thus break at their point of weakness. At this point the microneedles [4] are detached from said housing [2a] and remain in the skin. Thus, a single downward depression of one of the two housings [5a] results in microneedles [4] being extended into adjacent skin and then sheared away from the housing [2a]. Further, and notably, the device [1] has been designed with the force of the downward stroke ensuring rapid but comfortable insertion of said MNs into the skin each time the device is used thus ensuring the device provides a reliable and reproducible experience. Ideally, MN insertion is completed within about one second (the time it takes to activate the device) and therefore the process is designed to be quick, effective and easy for the user.
In yet a further preferred embodiment, the device comprises a removable shield or cap [12] adapted to prevent movement of the first part [2] or first housing [2a] with respect to said second part [5] or second housing [5a], for example, during transport.
According to a second aspect of the invention, there is provided a method for inserting microneedles into the skin of a subject, said method comprising the steps of:
Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, mean “including but not limited to” and do not exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
All references, including any patent or patent application, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. Further, no admission is made that any of the prior art constitutes part of the common general knowledge in the art.
Preferred features of each aspect of the invention may be as described in connection with any of the other aspects.
Other features of the present invention will become apparent from the following examples. Generally speaking, the invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including the accompanying claims and drawings). Thus, features, integers, characteristics, compounds or chemical moieties described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith.
Moreover, unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.
The Invention will now be described by way of example only with reference to the Examples below and to the following Figures wherein:
Referring now to the figures and, firstly, to
For convenience the device is shown as having a square cross-section although alternative shapes may be made, according to a user's requirements.
The internal components of the parts [2] and [5] are best described by way of the subsequent figures.
In
The carriers [3] are best shown according to the embodiment depicted in
With reference to the embodiment shown in
With reference to the embodiment shown in
With reference to
Notably, the carriers [3], or plates [7] when included, are movably mounted on supports [8] to move down with respect to housing [2a], via the contact of actuators [6] with plates [7].
Further, at least one carrier [3] or plate [7] is also moveably mounted on a support [8] to move laterally along support [8]. Thus, the carriers [3] or plates [7], can move downwardly on support [8] and slide laterally along support [8].
As will be appreciated, the number and shape of the moveable supports [8] can vary provided that both downward and lateral movement is achieved which, as will become apparent, is important to effect penetration of the microneedles and the detachment of the microneedles from the housing [2a].
The device [1] and more specifically the first housing [2a], is provided with a dampener or stopping member [10] which acts to limit the extent of downward movement of the moveable support [8] (and so carriers [3] and/or plates [7] of the microneedle array [9]) and thereby limit the extending of the microneedles [4] from housing [2a] and so the depth of penetration into skin. Thus, the location of stopping member [10] with respect to movable support [8] is chosen to ensure the correct depth of extension and so insertion of the microneedles [4]. Further, the said location of stopping member [10] affects the downward force so that carrier and/or plate movement cannot be so great as to break the microneedles [4] during injection or penetration into the skin. Conventional stopping mechanisms such as aligned runners on the moveable support and/or housing, or other stops may be used for this purpose and are known to those skilled in the art.
Moreover, and importantly, by controlling downward extension in this fashion, in particular stopping the downward motion before completion of the downstroke of actuators [6], enables the last part of the downward stroke to be converted into a lateral force which forces said carriers [3] or plates [7] apart whereby, typically, all of said carriers [3] or plates [7] move laterally.
Thus, a first part of the downward stroke extends carriers [3] or plates [7] outside housing [2a] and so into adjacent skin and a second part of the downward stroke moves the carrier [3] or plates [7] laterally, effectively snapping the microneedles [4] and bringing about detachment of same from the device [1].
Ideally, a number of carriers [3] or plates [7] move laterally in a first direction and another number move laterally in an opposite direction, with respect to said first direction, typically half move to the left and half move to the right. In this way, it has been found that lateral force can be exerted upon the needles [4] to ensure breakage.
Notably, where the carriers [3] or plates [7] are arranged in an aligned manner, movement of more than one movable support [8] brings about synchronised and ideally coordinated movement of said carriers [3] or plates [7] whereby said carriers [3] or plates [7] move simultaneously together from a retracted to an extended position.
As shown in
Referring to
Further, preferably the microneedles [4] are dissolvable/degradable or substantially dissolvable/degradable so that they have the ability to pass or dissolve into the surrounding environment, such as when in contact with an aqueous environment or the skin. As will be appreciated by those skilled in the art, dissolvable/degradable microneedles can deliver any agent coated thereon or therein into the skin. Accordingly, ideally, said microneedles [4] comprise at least one therapeutic, pharmaceutical or biological agent for delivery into the skin and release into the body. Said agent(s) include(s) active agent intended for topical, local, and/or systemic delivery. Generally, any drug or agent which can be delivered intradermally can be delivered using the microneedles. The agent includes any conventional medicament, therapeutic, contraceptive or cosmetic agent, vaccine, protein, antibody, or structural agent. Thus, microneedles [4] which are detached from the device and left embedded in the skin can provide sustained or extended release of agent(s) being delivered by the microneedles [4].
Typically, the device [1] is made from materials that are disposable thus the device is a single disposable unit that, once positioned, and the upper part is depressed, microneedles are inserted and detached in a single stroke. If present, an indicator signals the completion of the down stroke, and so also lateral stroke that occurs as a consequence. The applicator can then be disposed of, ideally after replacing the cap.
The invention therefore helps to solve the problems associated with agent or medicament delivery in a simple fashion that can be used by trained and even inexperienced staff, and advantageously can be used at home or in the field by a patient.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2010674.6 | Jul 2020 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2021/051672 | 7/1/2021 | WO |
