Total number of people suffering from diabetes in India is projected to increase from 31.7 million in 2000 to approximately 79.4 million in 2030. A drastic increase in the prevalence of this disorder is attributable to factors like an increase in the incidence of obesity, physical inactivity, burst in population growth, ageing and urbanisation. Consequently there is an exponential increase in the demand of a successful therapy which aids in achieving near normoglycaemic (blood glucose 70-120 mg/dl) levels leading to an increase in living standards of diabetics.

Unearthing of insulin in 1921 has proved to be a breakthrough in this field both for the treatment of type-I and type-II diabetes that is not controlled adequately by diet and/or oral hypoglycemic agents. Due to inherent physicochemical properties of insulin and its degradation in the gastrointestinal tract in the presence of proteases, calls for the need of a parentral mode of delivery. Subcutaneous delivery of insulin has been the mainstay in insulin delivery since its advent. The preparations delivered through this route are categorized on the basis of duration of action (i.e. rapid acting, short-acting, intermediate and long acting preparations) and based on origin (i.e. porcine or human). Injected rapid-acting insulin (e.g. aspart, lispro and glulisine) and short-acting insulin (regular insulin) are dispersed as clear solutions at a neutral pH and contain small amounts of zinc to improve the stability and shelf life. Intermediate acting NPH insulins are modified to provide a longer duration of action and are dispensed as suspension at neutral pH with protamine in phosphate buffer. Insulin detemir and glargine are the soluble long-acting insulins. Subcutaneous therapy basically aims at providing the normal basal as well as postprandial insulin, which is achieved by administering mixtures of various preparations or by a properly using a suitably designed dosage regimen. Syringes, pen devices and continuous insulin infusion pumps are used to facilitate ease of delivery of insulin through this route. The latter two devices possess an edge over syringes because they aid in better patient compliance, ease of portability and attainment of a near physiological insulin absorption pattern. Novo-Nordisk is a key player in the manufacture of these devices.

Although as on date bulk of marketed insulin preparations are delivered through the subcutaneous route, currently a great deal of stress is being laid on other modes of insulin delivery as well to evade the disadvantages of variable absorption of the hormone due to its delivery into the systemic circulation rather than portal circulation. The other noninvasive routes of insulin delivery being extensively explored are peroral, inhalation, pulmonary, transdermal, buccal, rectal and intravaginal.

Oral insulin delivery
Oral delivery of insulin, besides being a patient compliant route, possesses the potential advantage of mimicking near normal physiological insulin delivery pattern as normal insulin in this case is absorbed in the gastrointestinal tract from there it is released into the portal vein and carried directly to the liver before being delivered to the peripheral circulation. However, the efficacy of oral insulin delivery systems is strongly limited by a rapid degradation of this therapeutic peptide by intestinal proteases and a low absorption rate. So a lot of emphasis has to be laid on the formulation parameters like stability and permeability of the hormone from the gastrointestinal tract, while designing a successful oral insulin delivery system. A lot of research is being done on both the conventional systems and novel drug delivery systems to achieve this target.

Hydrogels of poly (methacrylic acid-g-ethylene glycol) were prepared by Nakamura et al., in 2004, using different reaction water contents in order to vary the network mesh size, swelling behaviour and insulin loading/release kinetics. It was observed that gels prepared with greater reaction solvent contents swelled to a greater degree and had a larger network mesh size. All of the hydrogels were found to incorporate insulin and protect it from release in acidic media. In these hydrogels, the structure of the polymer network exhibits pH-responsive swelling, which results in changes in network pore structure due to the reversible formation/dissociation of interpolymer complexes. This results in protection of the susceptible molecule from degradation in the lower pH of the stomach and aids its release in the lower part of the intestinal tract where the enzymatic activity is lower. Another significant approach for optimal delivery of insulin in the patient is the formulation of a controlled drug delivery device 'Insulin-Gated Delivery', which delivers insulin upon detection of an increase in glucose level in the bloodstream. Such a delivery system incorporates glucose-oxidase immobilized in a delivery-rate-controlling membrane of poly (methacrylic acid-g-poly (ethylene glycol)) copolymer surrounding a reservoir containing insulin. This non-swellable membrane acts as a fence to the insulin reservoir. Thus the glucose/glucose-oxidase reaction causes a lowering of the pH (~ 4.0) in the delivery system's microenvironment, resulting in a corresponding shrinkage of the polymer system leading to an increased release of insulin from the delivery system and vice-versa. The response rate produced by this system mainly depends on the size of the gates, the concentration of insulin, and the rate at which the gates open or close.

Transdermal route of delivery
Transdermal route of delivery closely mimics the benefits of intravenous drug infusion while overcoming its risks of necessary hospitalization and medical supervision of the medication. It is considered to be a potential route for delivery of protein-based pharmaceuticals, because of lower enzymatic activity at the application site. Due to larger size of the insulin molecule it has a limited permeability through the stratum corneum, so a lot of formulation parameters are to be optimized for sufficient delivery of insulin. Scientists are working on patches using electrical currents, ultrasound waves, and chemicals to help transport insulin through the skin. A transdermal periodic iontotherapeutic system was developed by Chien et al, early in 1989. It was considered to be useful in the systemic delivery of peptides like insulin which require delivery in a circadian pattern to simulate the physiological rhythm. Pillai et al, in 2004, demonstrated the potential of various commonly used solvents in the enhancement of the permeation of large peptides like insulin. In this study it was concluded that a synergistic enhancement with iontophoresis is achieved by combining solvents that act on intercellular lipids in the delivery of large peptides like insulin. Phosphagenics has developed and patented TPM-02/Insulin delivery system, the world's first transdermal insulin formulation. It claims that the product may have a blockbuster potential and it has received positive signs in the phase I studies. It is a suitable system for delivering both relatively small molecules as well as macromolecules up to 30,000 Daltons in size. TPM-02 is a multi-lamellar malleable vesicular carrier whose size can be tightly controlled which allows TPM-02 to be formulated in a range of sizes, from nanometres to microns in diameter.


Nasal route of delivery
Nasal route of insulin delivery possesses key advantages of rapid onset of action and relatively high bioavailabilities due to high vascularity, easy access and higher permeability of insulin through this route of application. The nasal cavity has a relatively lower surface area (~ 75 cm2) and only a small volume can be instilled in the cavity (0.1-0.5 ml), this makes the work of the pharma scientist quite challenging as a dosage form is to be developed which effectively delivers the required dose for therapeutic action. The physicochemical properties of the protein and peptide molecules, other than the molecular weight; also determine nasal absorption. Stability and permeability issues are also to be dealt with carefully while design of the delivery system, though many peptide drugs (up to 30,000 Dalton) have been successfully delivered through this route. The relative lack of success with this route is associated with the use of a higher concentration of absorption enhancer (nearly 1.0%), which cause toxicity to the nasal epithelium. Pillion et al, in 1994 has worked on a set of alkylglycosides and there use in the stimulation of the absorption of insulin from the nasal epithelium using rats. It was concluded that nose drops containing both a small amount of alkylglycoside (0.03-0.50%) and insulin (2 U regular porcine) caused a rapid decrease of blood D-glucose levels. Limitations associated with this route of delivery are spillage of nose drops and concomitant administration during sinusitis and rhinitis result in variable absorption. Nasulin is Bentley's patented intranasal insulin spray that addresses the need for an improved delivery method for insulin through this route. It is formulated as a stable liquid emulsion containing 1.0% human recombinant insulin, 2.0% CPE-215(R) excipient (Bentley's patented permeation enhancer), and surfactants as emulsifiers. CPE-215, has received GRAS (Generally Regarded as Safe) status from the FDA as a direct food additive, it has been shown to be non-irritating, stable and effective in gels, ointments, lotions and creams as well as intranasal spray formulations. Initial studies have indicated that Nasulin passes quickly through the nasal mucosa, delivering a larger amount of insulin for action, compared to other non-injectable delivery systems. It does not require constant refrigeration for use, and the delivery device is small, hence portable. Nasulin also holds a significant advantage for use in diabetes patients with Chronic Obstructive Pulmonary Disorder and asthma, as it does not enter the lungs, avoiding possible long-term effects on lungs function.

Pulmonary route
Pulmonary route is another noninvasive route, which has attracted the attention of scientists the world over. The US FDA provided regulatory approval of recombinant human insulin for inhalation Exubera in 2006. Exubera consists of blisters containing human insulin inhalation powder, which are administered using the Exubera Inhaler. Exubera blisters contain human insulin produced by recombinant DNA technology utilizing a non-pathogenic lab strain of Escherichia coli (K12). Each unit dose blister of Exubera contains a 1 mg or 3 mg dose of insulin in a homogeneous powder formulation containing sodium citrate (dihydrate), mannitol, glycine, and sodium hydroxide, it does not contain any propellant. After an Exubera blister is inserted into the inhaler, the patient has to pump the handle of the inhaler and then presses a button, causing the blister to be pierced. The insulin inhalation powder is then dispersed into the chamber, allowing the patient to inhale the aerosolized powder. Its onset of action is similar to that of rapid-acting insulin (range, 10-20 minutes), but its duration of action (~6 hours) is comparable to injected regular human insulin. In patients with type-1 diabetes, Exubera should be used in regimens that include a longer-acting insulin. In patients with type-2 diabetes, Exubera can be used as monotherapy or in combination with oral agents or longer-acting insulin. This route of insulin delivery possesses significant advantages of faster mode of action and is more patient compliant as it is 'pain-free'.

Buccal route
Buccal route offers several advantages over the oral route. On delivery through this route the drug is not exposed to destructive acidic environment of the stomach. It bypasses the first pass metabolism and a rapid serum concentration is achieved. In this case absorption primarily occurs by concentration gradient driven passive diffusion of nonionized species through the buccal epithelium. Buccal insulin is reported to be similar to inhaled insulin in some ways. Recently Generex has developed Oralin, this formulation delivers insulin directly into the mouth via RapidMist device, from where it is rapidly absorbed into the bloodstream through the buccal mucosa. Presently it is submitted for approval by Ecuadorian Ministry of Public Health for the treatment of both type-1 and type-2 diabetes. It is an encapsulated micellar system containing insulin and an absorption enhancer, which aids in opening of the paracellular junctions in the oral cavity as well as in the GI tract resulting in better therapeutic availability of insulin. Pozilli et al., in 2005 conducted a study to evaluate the metabolic effect of buccal spray insulin compared with subcutaneous regular insulin in patients with type-1 diabetes and observed insulin administered via the Buccal spray formulation is as effective as the subcutaneous route in lowering blood glucose levels.

Rectal route
Rectal route is a more recently exploited route for delivery of proteins and peptides. The major barrier associated with this route is the epithelial cell layers of the mucosal tissues, which can be overcome by addition of absorption enhancers. Barichello et al., in 1999 developed a Pluronic F-127 (PF127) gel containing unsaturated fatty acids as potential formulations for rectal insulin delivery. Water-in-oil-in-water multiple emulsions are also an effective dosage form as an enteral carrier of insulin because they could protect insulin against proteolysis. Onuki et al., in 2000 established rectal administration of insulin emulsion incorporating unsaturated fatty acids, particularly DHA and observed a marked hypoglycemic effect and insulin absorption from the rectum. But encouraging results are yet to be obtained with this route to proceed with clinical applications.

Potential advantages associated with the delivery of insulin to diabetics justify the need for continued efforts that are being put into the development of both pharmaceutical and biological approaches for the maximization of insulin absorption. Although delivery of insulin by the subcutaneous route (via syringes or pens or pumps) occupies the maximum market share of insulin delivery systems yet many approaches are being developed and are still under development stages to overcome the limiting factors associated with subcutaneous delivery of insulin. It is seen that majority of the techniques used so far to successfully target and to increase the bioavailability of this "vulnerable" molecule mainly include the use of absorption enhancers, protease inhibitors and novel bioadhesive and biodegradable polymers. The clinical success rate of all these approaches is yet to be established completely; still for more than two decades now, the medical community has been searching for a less painful and easier method for treating diabetes than insulin injections.

(The authors are with University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh)