**6.1 Microneedle types and their methods of transdermal delivery**

fabrication, shapes, dimensions, modes of application, etc. (Chabri et al., 2009).

Microneedles are available as both solid and hollow microneedles made of various materials (Figure 3). Till date, five methods of transdermal delivery mediated by microneedles have been attempted (Gill & Prausnitz, 2007): *Poke with patch approach*: It can be inserted into the skin to pierce the stratum corneum and create micro conduits through which drug can enter into the lower layers of the epidermis (Henry et al., 1998). *Coat and poke approach:* It involves coating the drug to be delivered around the surface of the microneedle. By inserting the microneedles through the skin, the drug coating dissolves off in the skin fluid and the dissolved drug diffuses through the skin into the blood microcirculation. The coating methods are used to roll coating, spray coating and dip coating (Gill & Prausnitz, 2006). *Dip and scrape:* The dip and scrape method involves placing the array in contact with the drug solution and then scraping multiple times across the skin to create microabbrassions (Mikszta et al., 2002). *Dissolving microneedles:* It is referred to microneedles made from a biodegradable polymeric material with the drugs encapsulated inside them. In this method, the drug is released in a controlled manner as the microneedle dissolves off when inserted into the skin (Lee W. J et al., 2007). *Injection through hollow microneedles:* This occurs where the microneedles are designed with holes at the centre or with side openings through which drugs are microinjected into the lower layers of the skin and then diffuses across the viable skin until it reaches the blood vessels in the dermis (Griss & Stemme, 2003).

Solid microneedles: These are easier to fabricate, have better mechanical strength and sharper tips as compared to hollow microneedles (Rhoxed et al., 2008a). Solid silicon microneedles have been widely used for the transdermal drug delivery studies (Donnelly et al., 2009; Haq et al., 2009). However, silicon is expensive, not biocompatible and brittle. Therefore it breaks easily during the penetration across skin (Chen et al., 2008). Polymer has been used as an alternative material because it is a cheaper and stronger material which could reduce tissue damage (Fernandez et al., 2009). Polymer increases the bluntness of the microneedle tip due to the low modulus and yield strength of polymer. Polymer microneedles have a main limitation with its mechanical properties which could cause needle failure during the penetration across skin (Park et al., 2007). Bevelled tip microneedles have been fabricated using biodegradable polymers (Park, 2004). Metal is the third material used to manufacture microneedles. It is mechanically strong and relatively cheap to produce.

Hollow microneedles*:* The purpose of this type of microneedles is to deliver drugs through the bore at the needle tip. This reduces the sharpness of needle tip which affect the penetration of this needle into skin. These issues have been resolved recently including openings at the side in the microneedles rather than at the bottom (Roxhed et al., 2008). These microneedles have their tip closed initially; however they can be opened on insertion into the skin where the tip dissolves in the high saline solution in the interstitial fluid. The tips can also be opened as a result of applied pressure. It has been proposed the use of

Chemical and Physical Enhancers for Transdermal Drug Delivery 415

diameter is enhanced when the skin is pre-treated with microneedles by adopting the poke with patch approach. Therefore, it seems to us that the delivery of micro and nano-particles is important in order to facilitate controlled/ delayed delivery after the drug is inserted into the skin (McAllister et al., 2003). *Insulin delivery:* Microneedles have been shown to deliver insulin with a significant biological effect as the blood glucose concentration was reduced by

Nanocarriers are so small to be detected by immune system and they can deliver the drug in the target organ using lower drug doses in order to reduce side effects. Nanocarriers can be administrated into the organisms by all the routes; one of them is the dermal route. The nanocarriers most used and investigated for topic/transdermal drug delivery in the pharmaceutical field are liposomes, dendrimers, nanoparticles and nanoemulsions (Table 7).

**Nanocarrier Size Preparation Methods Characteristics References** 

<50nm Sol-gel technique Nanometric particles,

Solid or hollow particles wich have entraped, binded or encapsulated drugs.

Similar to polymeric nanoparticles but made of solid lipids.

made up of inorganic compounds such as silica, titania and

Vesicles composed of

branched structures.

Multicomponent fluid made of water, a hydrophobic liquid, and one or several surfactants resulting in a stable system.

Made up of organic surfactants, precursors

and solvents.

alumina.

one or more concentric lipid bilayers, separated by water or aqueous buffer compartments.

Domínguez-Delgado et al., 2011; oppimath et al., 2001

Almeida & Souto, 2007

El Maghraby et al., 2008

Menjoge et al., 2010

Dan et al., 2010

Rzigalinski & Strobl, 2009

García-González, 2009

emulsification-diffusion, emulsification-diffusion by solvent displacement

emulsificationevaporation,

homogenization.

Sonication, extrusion, mozafari method

Dendrimers 3–10 nm Polymerization Macromolecular high

viral assembly, electrochemical assembly.

espontaneous systems.

substantial amount using microneedles.

Nanoparticles 10-1000 nm In situ polymerization,

50-1000 nm High-pressure

**7. Nanocarriers** 

Solid lipid nanoparticles

Inorganic nanoparticles

Liposomes 25 nm-

100 μm

Quantum dots 2-10nm Colloidal assembly,

Lipid globules 1-100 nm Emulsification

rotary drilling and mechanical vibration as methods to enhance insertion of hollow microneedles and the fluid infusion flow rate (Wang et al., 2006).

Fig. 3. Two dimensional view of hollow and solid microneedle.

#### **6.2 Microneedles manufacturing**

The methods that have been adopted for microneedle fabrication include wet etching, deep reactive ion etching (DRIE) (Teo et al., 2005), microinjection moulding (Sammoura et al., 2007), isotropic etching, isotropic etching in combination with deep etching and wet etching respectively, dry etching, isotropic and anisotropic, photolithography, thin film deposition (Moon & Lee, 2003), laser cutting (Martanto et al., 2004), and inclined LIGA process (Perennes et al., 2006). Studies have shown that factors such as microneedle geometry, coating depth on solid microneedle and skin thickness affect the drug delivery efficiency using microneedles (Al-Qallaf et al., 2009a; 2009b). To ensure that both the insertion and delivery occur at the right location, they should be sharp enough and at least 100μm in length (Stoeber & Liepmann, 2000).

#### **6.3 Microneedles applications**

*Vaccination against virus:* Researchers have recently presented microneedle patches as a better alternative for immunization. The vaccine can be coated unto microneedle array and presented as a simple patch which can allow patients to immunize themselves without the necessity for intense medical training (Stoeber & Liepmann, 2005). *Cutaneous fluid extraction and glucose monitoring:* A prototype of a disposable microneedle based glucose monitoring devices has been designed in which, the fluid extraction chamber attached to the microneedle can be connected to a sensing device which measures and indicates the glucose concentration in the body (Zimmermann et al., 2003). *Acne treatment:* The treatment is limited by the low rate of penetration of drugs through the stratum corneum. So, experiments have been carried out by applying the TheraJectMATTM dissolving microneedles containing API in a GRAS matrix to the surface of human skin with acne (Kwon, 2006). *Delivery of nanoparticles:* It was showed that the delivery of particles of 1μm in diameter is enhanced when the skin is pre-treated with microneedles by adopting the poke with patch approach. Therefore, it seems to us that the delivery of micro and nano-particles is important in order to facilitate controlled/ delayed delivery after the drug is inserted into the skin (McAllister et al., 2003). *Insulin delivery:* Microneedles have been shown to deliver insulin with a significant biological effect as the blood glucose concentration was reduced by substantial amount using microneedles.
