One of the new methods used to facilitate transdermal delivery of drug is using microneedles. Alza developed a transdermal technology called Macroflux® patch, which uses drug-coated microneedles to physically disrupt the outer layer of the skin, thus to enhance drug absorption. (Cefalu, 2004) Each patch includes an array of tens to hundreds of tiny needles. Once inserted into skin, the drug is released from the tip of the needles. Alza claims this technology is ‘needle-free’ and has optimal skin tolerability. Martanto et al.
(2004) did a study using laser-cut stainless steel microneedles to deliver insulin through the hairless skin of diabetic rats. Each array contained 105 microneedles, They reported the plasma concentration of insulin after delivery reached 0. 5-7. 4 ng/ml, enough to reduce blood glucose level as much as 80%. Nasal delivery Intranasal delivery of insulin has been investigated extensively since the 1980s, although it was first proposed as early as 1940s. An early studies showed that intranasal delivery of insulin was able to reduce blood glucose level in diabetic patients.
But the dose of insulin through intranasal delivery was approximately 20 times higher than that of subcutaneous insulin. Moreover, HbA1c level deteriorated slightly but significantly with intranasal insulin therapy compared to that with subcutaneous insulin therapy, despite the much higher dose. The poor bioavailability of intranasal delivery of insulin has been the major obstacle for this delivery approach to become a viable one. However, some studies published recently showed improved bioavailability obtained by formulating insulin with biocompatible polymers (Saudek, 1997)
Oral/inhalation delivery of insulin Oral delivery of insulin is obviously a very attractive approach to researchers due to unprecedented patient compliance. Scientists have been actively seeking different approaches to deliver insulin orally. For oral delivery, absorption could take place via the gastrointestinal tract, mucosa or lung alveoli (Cefalu, 2004). Gastrointestinal delivery. Insulin absorption through the gastrointestinal tract mimics the physiological enterohepatic transport of secreted insulin.
Many researchers and physicians believe that exogenous insulin going through the liver should be able to achieve better glycemic control than any other route of insulin administration since it is closer to the physiological secretion path. However, the prevalent protein-degrading enzymes and the acidic environment make the survival of insulin through the gastrointestinal tract practically impossible. Furthermore, insulin molecules are too big and hydrophilic to cross the mucosa. The first-pass metabolism removes about 50% of the insulin going through. As a result, the bioavailability of insulin is extremely low (i.
e. , < 0. 5%) (Cefalu, 2004). A handful of strategies have been investigated to overcome the bioavailability barriers, including use of protease inhibitors, permeation enhancers, enteric coating and polymer microsphere formulations. Often times two or more strategies are employed in one carrier system to protect the protein from being degraded and to facilitate the absorption. While most of the approaches are still being investigated in laboratories or pre-clinical stage, Nobex (Research Triange Park, NC) developed hexyl-insulin-monoconjugate-2 (HIM2) for oral delivery and has carried out phase II clinical trials.
A small polyethylene glycol 7-hexyl group is covalently linked to the free amino group on the LysB29 residue of human insulin via an amide bond (Gordon Still, 2002). The resultant conjugated insulin is more resistant to enzymatic degradation and better absorbed through mucosa compared to native human insulin. Clinical trials have suggested that oral HIM2 could effectively reduce fasting and postprandial hyperglycemia in both type 1 and type 2 diabetic patients. A bioavailability of approximately 5% from oral H1M2 was observed (Gordon Still, 2002).
Although promising, more convincing clinical trials need to be done before this conjugated insulin makes a medical reality. Buccal delivery. Insulin could be absorbed into blood stream rapidly through the buccal mucosa lining and in the oropharynx. The most developed buccal insulin formulation is Oralin from Generex Biotechnology. It is a liquid aerosol preparation of insulin delivered via the Rapidmist™ device, a metered dose inhaler. The device introduces an aerosol into the patient’s mouth, at a high velocity. (Cefalu, 2004)
Oralin was found to be effective in controlling postprandial hyperglycemia in both type 1 and type 2 diabetes. Oralin given to type 1 diabetic patients at a dose of 100 U before a challenge of the standard Sustacal meal (360 cal), had comparable blood glucose lowering effect to that of the subcutaneous regular insulin (10 U). When tested in type 2 diabetic patients, similar results were observed. Oralin was also added to the treatment of subjects with type 2 diabetes in whom oral hypoglycemic agents were ailing. The addition of Oralin was beneficial in terms of regulation of postprandial glucose (Guevara-Aguirre et al., 2004).
However, the trials demonstrating the effectiveness of Oralin were all carried out in relatively small number of subjects. Long-term safety and side effect profiles have not been addressed. Pulmonary delivery. The lung has exceptionally large absorptive surface area (up to 100 m2) due to millions of alveoli in the lung. Only a very thin cell layer (about two cells) separates the blood in the pulmonary capillaries and the inside of alveoli, therefore the permeability of alveolar surface is high. All these features make the lung a site of efficient entry into bloodstream (Patton et a., 2004).
The concept of inhaled insulin was brought up around eighty years ago, soon after the first use of insulin in human. However, limitation of bioavailability, variability and portability of the inhaler at that time made it infeasible. Development of the insulin formulations and the inhaler technology has driven the pulmonary insulin delivery to a completely new stage. The pulmonary route of insulin administration has received most attention amongst all the non-invasive alternatives that have been evaluated and it is the most promising approach to make a commercial product at this time.
(Patton et al. , 2004) However, inhaled insulin systems are far from perfect. Many factors may have an impact on the delivery of insulin by inhalation. The ability of the device to deliver insulin deep in the lung is a variable, causing poor reproducibility. The control of the particle size of the insulin formulation is fundamental to the delivery efficiency. The optimal particle size for delivery to the alveoli has been established to be 1 to 3 nm in aerodynamic diameter (Patton et a. , 2004).
Liquid insulin formulation may provide better absorption, while dry powder form has better room-temperature stability, less susceptibility to microbial growth and ability to deliver higher dose per inhalation (Patton et a. , 2004). Other factors such as particle velocity, inspired volume, inspirator/ time, breath-hold time will affect the delivery efficiency of insulin to the lung. Other methods of delivery Insulin eye drops have been investigated as a delivery alternative. Studies in animals as well as human subjects demonstrated absorption of insulin and lowering of blood glucose levels using insulin eye drops.
Absorption enhancer, usually a surfactant such as saponin, was necessary to ensure the effectiveness of insulin absorption. However, non-irritating absorption enhancers need to be identified in order for insulin in eye drop form to become clinically feasible (Bartlett et al. , 1994). Delivery of insulin through rectal or vaginal route has been reported, mostly in the 1980s. (Saudek, 1997) Insulin administered as a suppository was evaluated in both animals and human subjects. Blood glucose levels were reduced after administration.
Vaginal insulin has only been reported in animals. Both routes attracted little interest among researchers, suffering low bioavailability and possible sociopsycho controversy.
References
Bartlett, J. , Slusser, T. , Turner-Henson, A. et al. (1994). Toxicity of insulin administered chronically to human eye in vivo. J Ocul Pharmacol 10, 101-107. Beals, J. & Kovach, PM. (1997). Insulin. In Pharmaceutical Biotechnology: An Introduction for Pharmacists and Pharmaceutical Scientists (Crommelin, DJ & Sindelar, RD, eds), Harwood Academic Publishers, Amsterdam, pp. 229-238.