Microneedles for drug delivery: trends and progress

Figures & data

Figure 1. Cross section through human skin (A) intracellular, (B) hair follicles and sweat glands, (C) direct pathway through the SC and, (D) depicts the micron sized holes that can be created by MNs upon the skin (modified from Shah et al. (2011)).

Table 1. Examples of enhanced protein/peptide delivery to and across the skin.

Protein/peptide	Delivery method	Main outcome	References
Bovine serum albumin	Polymeric microneedles	All drug released in six hours for in vitro permeation studies	Kochhar et al., 2012
Bovine serum albumin	Microneedles, ultrasound	BSA permeability of 1 µm/s is achieved with a 1.5-mm height microneedle and 15 W ultrasound output	Han & Das, 2013
Bovine insulin and bovine  serum albumin	Microneedles coupled with iontophoresis	MN design containing 361 MNs/cm^2 of drug permeation in six hours on neonatal porcine skin in vitro	Garland et al., 2012
Botulinum toxin A	Stainless steel microneedles	Efficient diffusion through the dermis	Torrisi et al., 2013
Hepatitis B surface antigen	Elastic liposomes	Systemic and mucosal antibody response elicited in mice	Benson & Namjoshi, 2008
Hepatitis B virus DNA vaccine	Jet propulsion (Powderject)	Application to healthy human volunteers resulted in both humoral- and cell-mediated immune responses	Benson & Namjoshi, 2008
Insulin	Insulin-loaded dissolvable microneedle made of starch and gelatin	Dissolved in five minutes in rats to relative pharmacological availability and relative bioavailability of 92%	Ling & Chen, 2013
Influenza subunit vaccine	Microneedles delivery	Application to intramuscular injection in guinea pigs. Hemagglutinin concentrations as high as 20 mg/ml	Kommareddy et al., 2013
Measles	Microneedles delivery	Measles was able to be coated and dried onto MN. Vaccine delivery into rats was comparable to using hypodermic needles, which gave similar antibody tilters	Edens et al., 2013

Figure 2. Forecasted, fitted and observed results on the trend of publications on microneedles using the keyword “microneedle”.

Figure 3. Forecasted, fitted and observed results on the trend of publications on hollow microneedle using the keyword “hollow microneedle”.

Table 2. Methods of fabricating solid MNs.

Methods	Materials	Dimensions (µm)	Advantages	Disadvantages	References
Separable dissolving arrow heads	• (Polydimethylsiloxane (PDMS) Sylgard 184,), • Metal shaft • Water-soluble excipients – PVP, sucrose • PLGA	600 μm-long PVP/PVA arrowhead capped onto a metal shaft with an exposed length of 600 μm and a 100 μm overlap.	• Rapid (1–5 s)/painless drug/vaccines delivery • PDMS: inert/non-toxic/non flammable Rapid (1–5 s)/painless drug/vaccines delivery, convenient/safe/potential self-administration, can allow controlled release of active ingredient • Advantage over coated needles-elimination of bio-hazardous waste, allow self-administration • Does not require extended patch wearing even for long duration of drug releases. • PDMS: inert • PDMS: non-toxic • PDMS: non flammable	• Difficult insertion into skin as requires wider needle geometry (non-blunt shaft) • Non reusable • Fibrotic reaction	Chu & Prausnitz, 2011; Backovic et al., 2007
Dissolving	• Mixture insulin, water, dextrin	Basal diameter: 3.24 ± 0.16 and 0.55 ± 0.03 mm	• Bio-compatible	• Produce bio hazardous sharp waste • Large tipped	Ito et al., 2006
Pyramidal dissolving polymer	• Polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP) • A = pyramidal MN • B = extended pyramidal MNs • C = pedestal MNs	Base width × base depth × needle height: A: 300 µm× 300 µm× 600 µm. B: 300 µm× 300 µm× 900 µm. C: 340 µm× 340 µm× 900 µm) 10 × 10 array	• Ability to increase drug capacity and localize to the MN tip • Allowed a deeper insertion • Higher increase of drug to be dissolved	• Produce bio hazardous sharp waste	Chu et al., 2010
Deep reactive ion etching	• Chromium • Silicon wafers	120 µm length, < 1 µm tip diameter	• Mechanically strong	• Reusability questionably • Top 5–10 µm of MN damaged for a few samples	Henry et al., 1998
Dissolving. fabricated by a drawing technique to create a sharp tip	• Maltose	1200 µm length 60 µm tip diameter	• Requires no moulds, therefore no sharp waste	• Complicated process	Lee et al., 2011
Cutting metal using infrared laser, manually bending the MN structure, electropolished	• Metal	1000 µm length, 50 µm× 200 µm cross section at base, tapered to a sharp tip (angle 20°), 106 array	• A short MN insertion time was better than a longer insertion time to facilitate drug permeation	• Insertion of large array was difficult by hand without external device • Strong acids used	Martanto et al., 2004
Silicon master mould to make PDMS inverse mould	• Sugar glass MN: • Trehalose/mannitol (50:50 w/w) • Trehalose dehydrate/sucrose (75:25w/w) • Trehalose/sucrose (75:25 w/w) • Trehalose/sucrose (50:50 w/w) • 2% (w.w) methylene blue	200 µm base 20 µm tip 300 µm height	• Fast dissolution of drug into skin • Use of simple sugars to create biodegradable MNs	• MN patch needles to be left on the skin for potentially over 20 min	Martin et al., 2012
Stainless steel MN produced by chemical etching	• Stainless steel	750 μm height 200 μm × 50 μm at the base. Single row of five MNs	• Dose of measles vaccine is small, therefore the dimensions of the MN are sufficient to allow coating and delivery of the vaccine • Needles long enough for rat dorsal thickness (700 μm–1000 μm) penetration • Cost effective manufacturing	• Produce bio hazardous sharp waste	Edens et al., 2013
Dissolving MN	• Starch/gelatin (1:1 ratio) • PDMS mould	600 μm height 300 μm base 5 μm tip	• Rapid dissolution of five minutes was achieved • Pharmacological activity retain in the starch/gelatin	• Time to reach minimum plasma glucose level slightly longer for MN than for subcutaneous injection of insulin	Ling & Chen, 2013

Figure 4. SEM images of various microneedles: (A) solid conical shaped microneedle (Henry et al., 1998), (B) solid microneedle next to a 27-gauge syringe (Martanto et al., 2004).

Figure 5. Forecasted, fitted and observed results on the trend of publications on solid microneedle using the keyword “solid microneedles”.

Figure 6. Images of an arrow head microneedle (Chu & Prausnitz, 2011).

Figure 7. Super-short microneedles. SEM images of (A) a single sharp tipped super-short microneedle, (B) a single flat tipped super-short microneedle and (C) an angled view of a flat tipped super-short microneedle array (Wei-Ze et al., 2010).

Table 3. Parameters of super short MNs (Wei-Ze et al., 2010).

Method	Materials	Dimensions (µm)	Advantages	Disadvantages
Sharp tipped super short microneedles	Microneedle: Silicon with 30% potassium hydroxide Patch: • Backing: polyethylene • Adhesive: polyisobutylene	75	• Strong material which does not break with insertion forces exceeding 8 N • Reusable	• Permeability of drug is lower compared to flat tipped microneedle • Skin folding shown upon insertion of needle compared with flat-tipped microneedle
Flat tipped super short microneedles	Microneedle: silicon with 30% potassium hydroxide Patch: • Backing: polyethylene • Adhesive: polyisobutylene	80	• Increase permeability in skin compared to sharp tipped microneedle • Decreases skin barrier function • No skin folding shown upon insertion of needle compared to sharp tipped microneedle • Strong material, which does not break with insertion forces exceeding 8 N • Reusable	N/A

Figure 8. Forecasted, fitted and observed results on the trend of publications on dissolvable microneedle using the keywords “dissolvable microneedle”.

Figure 9. Division of patents filed based on type of MNs (Bariya et al., 2011).

Table 4. Example patents on microneedles technology.

Patent number	Date of filing	Applicant	Key invention	Country	References
US 2010042050	16 April 2007	Nemaura Pharma Ltd, USA	Applicator for microneedles.	USA, European, Japan, China, India	Chowdhury, 2010
WO 2011016230	4 August 2010	Medrx Co., Ltd., Japan	Provided is a microneedle device which protects microneedles, has an easily portable shape, is free from such problems as breakage of fine needles in the step of puncturing the skin with the microneedles, and ensures appropriate skin puncture to administer a drug.	Japan	Kobayashi & Hamamoto, 2011
WO 2011084951, US 20110172645	4 January 2011, 8 January 2010	Ratio, Inc., USA	Microneedle configured to facilitate delivery of the drug to the subject. The microneedle includes a tip portion and is moveable from an inactive position to an activated position.	USA	Moga et al., 2011
WO 2011014514	27 July 2010	3 M Innovative Properties Company, USA	This disclosure relates to apparatus, assemblies, combinations and methods for infusing fluids by hollow microneedles.	USA	Gonzalez et al., 2011
CA 2696810 JP 2011078618 WO 2011043086 AU 2010201434 KR 2011067009 EP 2343102 A1	15 January 2010	Bioserentach Co. Ltd., Japan	Microneedle sheets are produced by injecting a needle raw material into a stamper formed with a concavity in a base material.	Japan	Honda et al., 2011
WO 2013096026	12 December 2012	3 M Innovative Properties Company, USA	Assembly of a microneedle adhesive patch. The assembly can include a backing and an adhesive and a matrix coupled to the backing.	USA	Cantor & Stockholm,2013
WO 2013066262	2 November 2011	Singapore	Invention relates to plastic microneedle strips that are used in TDD for increasing the DD rate through the skin.	Spain	Lim et al., 2013

Table 5. Example patents on methods of microneedle fabrication.

Patent number	Date of filing	Applicant	Key invention	Country	References
EP 2289843	31 August 2009	University College Cork-National University of Ireland, Cork, Ireland.	The invention relates to a method of fabricating a microneedle device of the type comprising an array microneedles on a flexible polymer support layer.	European	Cork University Patent EP 2289843
JP 2011083387	14 October 2009	Kyushu Institute of Technology, Japan; Nichiban Co., Ltd.	Manufactured. by (1) performing Bosch process to a Si wafer to form a Si microneedle having a tapered tip and a columnar part with the same diameter or a decreasing diameter in the longitudinal direction, etching the tip with an etching solution and/or a reactive radical.	Japan	Akiyoshi, 2012
CN 102000020	17 November 2010	Beijing Pharmaceutical Research Institute, Henan Lingrui Pharmaceutical Co., Ltd., People Republic of China; Beijing Lingrui Hi-tech Co., Ltd.	The title polymer (molecular weight: 1000–1000 000) is selected from poly(p-dioxanone) or p-dioxanone containing copolymer (containing p-dioxanone 10–100 wt.%), such as poly(p-dioxanone-lactide), poly(p-dioxanone-glycolide), etc.	China	Huizhen et al., 2011
CN 103263727	22 May 2013	Tsinghua University, People Republic of China.	A metallic microneedle array, including substrate and a metal sheet fixed on the surface of the substrate.	China	Yue & Wang, 2013
US 20130030374 A1	11 October 2012	Toppan Printing Co., Ltd.	Microneedle including forming a plurality of first linear grooves on a substrate in parallel to one another along a first direction using grinding and forming a plurality of second linear grooves on the substrate in parallel to one another in a second direction intersecting the first direction using grinding.	USA	Sugimura et al., 2013
CN 103181887	30 December 2011	Shanghai No.7 People’s Hospital, People Republic of China.	Invention relates to triamcinolone acetonide biodegradable maltose microneedle array which contains (1) triamcinolone acetonide or its pharmaceutically acceptable salt and (2) maltose or its hydrate, wherein the length of microneedle is 800–1500 µm, the diameter of the microneedle is 100–300 μm and array d. is 9–100 needles/cm^2.	China	Zhang & Wu, 2013

Table 6. Patents on chemicals used for microneedle transdermal delivery system.

Patent number	Date of filing	Applicant	Key invention	Country	References
GB2472778A	17 August 2009	PANGAEA LAB LTD	Microneedle roller.	Great Britain	Saacs & Cobbledick, 2011
WO 2011026144 or S 20110052694	31 August 2009	AllTranz Inc., USA	DD system for pharma-active ingredients (e.g. cannabidiol and prodrugs of cannabidiol).	USA	Stinchcomb et al., 2011
US 20110118560, US 20110118656, US 20110117150, US 20110118652, US 20110118696, US 20110118653, US 20110118697, US 20110118698, US 20110118652 US 20110118656	13 November 2009, 19 February 2010, 9 March 2010	Searete LLC, USA	Provides one or more medicines to mammalian subject.	USA	Eckhoff et al., 2011
CN 101991846	17 November 2010	Chifeng Boen Pharmaceutical Co., Ltd., People Republic of China	The invention relates to inactivated vaccine for immunoprophylaxis of bovine mastitis caused by Escherichia coli and its preparation method.	China	Li et al., 2011a
US 20130171722	3 January 2012	City University of Hong Kong, Hong Kong	Injection of a substance into a subject including elongate non-hollow micro-nanoneedles for delivering bioactive substance including drug and gene molecules such as plasmid DNA, siRNA, miRNA and shRNA.	USA	Chen & Zhang, 2013

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