WO2009081125A2

WO2009081125A2 - Aerosol coating of microneedles

Info

Publication number: WO2009081125A2
Application number: PCT/GB2008/004205
Authority: WO
Inventors: James Caradoc Birchal; Glyn Taylor; Christopher John Martin
Original assignee: University College Cardiff Consultants Limited
Priority date: 2007-12-21
Filing date: 2008-12-18
Publication date: 2009-07-02
Also published as: GB0725017D0; WO2009081125A3

Abstract

A method for coating microneedles or a microneedle array with a selected agent using an aerosolised technique.

Description

Aerosol Coating of Microneedles

The invention relates to a method of coating microneedles and microneedles when coated by the aforesaid method.

In recent years microneedles have emerged as technology that exists at the interface of engineering and biological sciences. They have been widely reported as an exciting alternative to conventional 'needle and syringe' injection. Microneedles, so termed as they generally range from 100 to 1000 μm (typically between 200 and 600 μm) in length, are designed to perforate the external skin barrier layer, the stratum corneum. The stratum corneum provides a protective and defensive barrier that represents the upper, outermost part of the epidermis, being 10-20 micrometres thick. It consists of flattened corneocytes surrounded by a lipid matrix. The waterproofing barrier property of the stratum corneum is imparted by the intercellular multi-lamellar lipid sheets that surround individual corneocytes. The corneocytes contain densely packed insoluble keratin filaments and, although functional enzymes are present, they are regarded as non-viable due to the absence of functional organelles and their inability to regenerate. The stratum corneum is, however, in a dynamic state, with continuous renewal and modification of the extra-cellular barrier lipids and controlled desquamation of corneocytes being facilitated by a host of different enzymes.

In order to provide a direct and controlled route of access for therapeutic materials to the underlying viable tissue layers this stratum corneum must be penetrated.

In some cases microneedles can be manufactured so that the length of each microneedle is such that the depth of penetration causes minimal damage to the nerve fibres and blood vessels that reside primarily in the sub-epidermal layer, therefore, the delivery of both small and large molecular weight medicaments into the skin can be achieved without causing pain or bleeding at the site of the application.

Microneedles provide the drug-delivery specialist with a fresh opportunity for administering a range of therapeutics to and through skin, with the methodology conferring a number of advantages compared with alternative topical or transdermal approaches, or other physical cutaneous delivery methods. These include direct and controlled delivery of the medicament to targeted skin layers, rapid exposure of large surface areas of epidermis to the delivery agents (microneedle arrays can contain over 1000 microneedles), effortless, convenient and painless delivery for the patient, the ability to manipulate the drug formulation (e.g., solution, suspension, emulsion, dry powder and gel) for optimum effect, the use of concomitant delivery methods such as transdermal patches, and minimal invasiveness suited to patient self- administration without the need for medical supervision. A further important advantage in microneedle use lies in the ability to adapt the composition and dimensions of the needle to facilitate the delivery of a range of therapeutics including conventional drug • molecules, macromolecules, nanoparticles and vaccines.

Microneedle arrays comprise, as the term describes, an assembly of micro-scale needles (either solid or hollow) that can penetrate the stratum corneum layer in skin to produce micro-scale channels that project into the underlying tissue layers.

Microneedle arrays can be made from fabrication of silicon wafers using a lithographically patterned mask. Microneedle structures can also be fabricated from metals and glass. Microneedle templates can then further be used to prepare replicates by the moulding of a suitable polymer or other material.

Once the microneedle arrays have been manufactured there is a need to evenly and reliably coat each needle with a suitable therapeutic. Moreover, in some instances, the therapeutic agent to be applied to the microneedle array may be extremely costly and therefore there is a need to avoid waste through inadvertent coating of the microneedle support substrate i.e. the part of the device that is not to be inserted into the skin.

Currently microneedles are dip-coated by insertion of the needle tips into a solution, suspension or emulsion of the active therapeutic. This process is labour-intensive, time-consuming, irreproducible and difficult to control. Moreover concentric coatings of a range of medicaments would involve reintroducing the drug coatings into liquid, thereby potentially removing previously coated material by resolvation, resuspension or redispersion in the liquid.

We have therefore developed a new method of coating a microneedle array which overcomes the problems associated with the prior art. According to a first aspect of the invention there is provided a method for coating a plurality of microneedles constituting a microneedle array comprising:

(a) dissolving, suspending or dispersing an agent to be coated on said microneedles in a selected fluid;

(b) aerosolising the said fluid; (c) exposing the said microneedle array to the said aerosolised fluid whereby the aerosolised agent coats the said microneedles.

We believe that the aerosolisation of the agent presents the agent in a fine particulate spray and thus provides for much more even and equal coating of the microneedles in the array. Further, aerosolising the agent ensures that it is the microneedle tips that are coated with the agent rather than the underlying substrate. This is due to the inverted geometry of the exposed microneedles and gravitational forces; the agent preferentially coats the microneedle tips.

In a preferred method of the invention part (c) above is followed by exposing the microneedle array to a selected temperature in order to encourage evaporation or solidification of the coating agent on the said microneedles.

The viscosity of the said fluid for coating relates directly to the thickness of the coat deposited on the microneedle. It is therefore advantageous to use a viscosity enhancer in the said fluid and an example of such a viscosity enhancer is carboxymethylcellulose (CMC). Typically, we use CMC at 1% w/v. However any one or more of the following viscosity enhancers can be used.

• Natural hydrocolloids

Acacia, tragacanth, alginic acid, carrageenan, locust bean gum, guar gum, gelatin. • Semisynthetic hydrocolloids

Methylcellulose, sodium carboxymethylcellulose

• Synthetic hydrocolloids Carbopol®

• Clays Bentonite, Veegum®

Additionally, any viscosity enhancer can be used at a concentration of 0.1 to 50% w/v and most preferably 0.5 to 5% w/v. Advantageously, additionally or alternatively, we use a surface active agent such as PF68 Pluronic Surfactant and ideally at a concentration of 0.8% w/v. The surfactant affects the surface tension between the microneedle and the coating liquid, promoting contact between the surfaces.

Notably any one or more of the following known surface active agents may be used or indeed others known to those skilled in the art.

Ionic: Anionic (based on sulfate, sulfonate or carboxylate anions) :

Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfate salts

Sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES)

Alkyl benzene sulfonate Soaps, or fatty acid salts

Cationic (based on quaternary ammonium cations) :

Cetyl trimethylammonium bromide (CTAB) a.k.a. hexadecyl trimethyl ammonium bromide, and other alkyltrimethylammonium salts Cetylpyridinium chloride (CPC)

Polyethoxylated tallow amine (POEA) Benzalkonium chloride (BAC) Benzethonium chloride (BZT) Zwitterionic (amphoteric) :

Dodecyl betaine

Dodecyl dimethylamine oxide

Cocamidopropyl betaine

Coco ampho glycinate

Nonionic :

Alkyl poly(ethylene oxide)

Copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially called Poloxamers or Poloxamines) Alkyl polyglucosides, including:

Octyl glucoside

Decyl maltoside

Fatty alcohols

Cetyl alcohol Oleyl alcohol

Cocamide MEA, cocamide DEA, cocamide TEA The above one or more surface active agents can be used at a concentration of 0.1 to 50% w/v and most preferably 0.5 to 5% w/v.

In a yet further method of the invention the aerosolised agent is recycled for re-use in part (b) above, either for re-use in the same or a different coating process.

Typically a coating fluid comprises 0.5-5% w/v CMC and 0.5-5% w/v PF68 and, ideally, 1 % w/v CMC and 0.8% w/v PF68.

According to a further aspect of the invention there is provided a microneedle or. microneedle array coated with an agent, ideally a therapeutic agent using the above described method.

An embodiment of the invention will now be described, by way of example only, with reference to the following Figures wherein:

Figure 1 shows the apparatus used for undertaking the method of the invention; Figure 2 shows microneedle tips coated using the method of the invention;

Figure 3 shows images of two microneedle arrays, 4 needles per array coated using the method of the invention;

Figure 4 shows the surface of the skin after exposure to the microneedle array and so deposition within the skin of the agent that has been delivered; and

Figure 5 shows an image of a microneedle tip when coated with methylene blue using a conventional dip-coating technique.

Referring now to Figure 1 there is shown an apparatus for undertaking the method of the invention. The apparatus comprises a heating mechanism, in this instance a hotplate 1 over which there is positioned a heat chamber 2 that is in fluid communication with a conventional aerosolisation device 3. The heat chamber 2 comprises an orifice (not visible) through which a microneedle array passes in order to be suspended, with the microneedles pointing downwards, within the heat chamber 2. With the needles directed downwardly, a better distribution of aerosolised materials can be obtained during the coating process.

A fluid preparation to be aerosolised is inserted into the aerosolisation device and following activation of this device an aerosolised fluid is propelled towards the suspended microarray. Typically, the hotplate is set at 200⁰C and, having reached temperature, the microarray is subjected to five minutes of exposure to the aerosolised fluid followed by five minutes of drying time. The microneedle coated in accordance with this methodology is shown in Figure 2.

Shown in Figure 3 are the results of an alternative methodology wherein a strip of 4 microneedles is coated at 200⁰C but this time the microneedles were exposed to an aerosolised fluid for ten minutes followed by rotation of the microarray through 18O⁰C and exposure for a further ten minutes to the aerosolised fluid. After this time the microneedle array was allowed to dry for a further ten minutes. Shown in Figure 4 are the results of applying the microneedles shown in

Figure 3 to human skin. As can be seen, the coating on the needles penetrates the stratum corneum and disperses throughout the epidermal layers of the skin.

In the above methodologies each of the aerosolised solutions contain 1 % w/v CMC and 0.8% w/v PF68. However any one of more of the viscosity enhancers described herein at a concentration of 0.1 to 50% w/v and, ideally, 0.5 to 5% w/v may be used. Additionally a surface active agent, or a combination of surface active agents described herein at a concentration of 0.1 to 50% w/v and, ideally, 0.5 to 5% w/v may be used. The amount of therapeutic agent to be used in the aerosolised fluid varies according to the amount of therapeutic to be delivered. Based on patches containing 50-1000 microneedles, doses up to 1 mg should be possible as coatings. Needle shapes could be coated include conical, a pyramid or parallel sided shapes. In an example a fluid containing 50% therapeutic agent and 50% formulation excipients when deposited as a 10 to 20 μm thick coating on a microneedle of 50,000 μm² surface area will deliver in the order of 0.5mg of the agent for a suitable array.

As those skilled in the art will appreciate where more or less therapeutic is to be administered the amount of therapeutic in the fluid coating will be modified accordingly or the thickness of the coating could be changed.

Figure 5 shows an image of a microneedle tip that has been coated with a therapeutic agent using a conventional dip-coating technique. As can be seen the coating is uneven and incomplete; parts of the microneedle tip lack coating with any agent and rather than providing for a uniform coating discrete droplets are formed on the microneedle surface. This is in contrast to the image shown in Figure 2 where the entire tip surface is coated with the aerosolised fluid.

The technique described above has particular benefit when used to coat microneedles having a length which is in the order of from 100 to 1000 μm, (typically between 200 and 600 μm). Dip coating requires extremely precise clipping height control or masking of the microneedle base plate in order to prevent coating of that base plate from being coated with potentially expensive or rare therapeutic agents. Such masking is a technically difficult step because alignment of the mask with the needles is required when the mask is fitted over the microneedle array. Also, the mask will have a certain thickness and that thickness obscures the needle bases. Thus the whole needle length is not available to be coated. It is the obscured needle bases which have the greatest surface area to carry the therapeutic so dipping is not an efficient coating method. Where the present method is employed and the mirconeedles are directed downwardly, the needle base is approximately horizontal and facing downwardly. The needles are consequently preferentially coated and the base surface has little or no coating. Thus a more efficient coating method is realised.

Claims

1. A method for coating a plurality of microneedles constituting a microneedle array comprising:

(b) aerosolising the said fluid;

(c) exposing the said microneedle array to the said aerosolised fluid whereby the aerosolised agent coats the said microneedles.

2. A method according to claim 1 wherein part (c) above is followed by exposing the microneedles of the microneedle array to a selected temperature in order to encourage evaporation or solidification of the coating agent on said microneedles.

3. A method according to claims 1 or 2 wherein said selected fluid includes a viscosity enhancer.

4. A method according to claim 3 wherein said viscosity enhancer is selected from the group consisting of natural hydrocolloids, semi-synthetic hydrocolloids, synthetic hydrocolloids or clays.

5. A method according to claim 4 wherein said viscosity enhancer is carboxymethylcellulose (CMC)i

6. A method according to claims 3, 4 or 5 wherein said viscosity enhancer is used at a concentration of 0.1 to 50% w/v.

7. A method according to claim 6 wherein said viscosity enhancer is used at a concentration of 0.5 to 5% w/v.

8. A method according to any preceding claim wherein said selected fluid comprises a surface active agent.

9. A method according to claim 8 wherein said surface active agent is ionic, cationic, zwitterionic (amphoteric), or non-ionic.

10. A method according to claim 9 wherein said surface active agent is

Pluronic Surfactant (PF68).

11. A method according to claims 8-10 wherein said surface active agent is present at a concentration of 0.1 to 50% w/v.

12. A method according to claim 11 wherein said surface active agent is present at a concentration of 0.5 to 5% w/v.

13. A method according to any preceding claim wherein the aerosolised agent is recycled for re-use in part (b) above.

14. A method according to any preceding claim including the step of directing the microneedle array downwardly during at least part of the coating process.

15. A microneedle or microneedle array coated with an agent according to the method of any preceding claim.

16. A microneedle or microneedle array according to claim 15 wherein said agent is a therapeutic agent.