According to the American diabetes association, diabetes affects over 20 million children and adults, or 7% of the population, in the United States, nearly a third of who are currently unwires that they have hyperglycaemia. Approximately 1.5 million new cases of diabetes are diagnosed each year in the united state and diabetes is the leading cause of end stage renal disease, adult-onset blindness, and no traumatic lower extremity amputations. A staggering 54 million adults in this country have “pre-diabetes”, which is defined as elevated blood sugar that does not reach the criterion accepted for an outright diagnosis to diabetes. The total no. of people with diabetes worldwide was estimated to be between 151 million and 171 million at the turn of the century, and is expected to rise 366 million by 2030. The prevalence of diabetes is increasingly sharply in the developing world as people adopt more sedentary life style, with India and China the largest contributors to the world’s diabetic load [3]. Transdermal system is ideally suited for diseases that demand chronic treatment [4]. In spite of the high cost of transdermal patches for diabetes treatment, antidiabetic patches with established dosage forms reduced the occurrence of hospitalization and diagnostic costs. Recently, different oral antidiabetic sulphonylurea drugs have been subjected to extensive investigations for their appropriateness to be delivered via transdermal route e.g., glibenclamide, chlorpropamide [5-7], gliquidone [8] and glipizide [9, 10], and glimepiride [11]. Glipizide is a potent, second generation oral sulphonylurea drug. Being a weak acid (pka=5.9), glipizide is better absorbed from acidic medium; however, at very low pH levels, the solubility of glipizide is minimal [12]. This limited aqueous solubility causes large variations in bioavailability and, in the presence of renal or hepatic insufficiency, alcohol and other drugs, severe and prolonged hypoglycaemia may occur [13]. Glimepiride is a new third generation sulphonylurea oral hypoglycaemic agent. It has been proposed for the treatment of type 2 diabetes, whenever blood glucose levels cannot be adequately controlled by diet, physical exercise and weight reduction alone. Glimepiride enhances the normal action of insulin on peripheral glucose uptake (insulin-sensitizing effect). It also enhances peripheral glucose uptake and inhibits glucose output (insulin-mimetic effects). It directly increases the number of glucose transporters in the plasma membranes of muscle and fat cell. In comparison to other sulphonylurea antidiabetic drugs, glimepiride expresses an insulin-sparing effect and minimal interaction with the cardiovascular system [14, 15]. This is the various developed antidiabetic drug in the transdermal patch form. Currently a number of antidiabetic transdermal patches are introduced into the pharmaceutical market. This article represents antidiabetic transdermal patches as reported in various pharmaceutical journals.

Permeation through skin:

The major problem associated with the dermal delivery system is the excellent barrier property of the skin. This resides in the outermost layer, the stratum corneum. This unique membrane is only some 20 μm thick but has evolved to provide a layer that prevents us from losing excessive amounts of water and limits the ingress of chemicals with which we come into contact. The precise mechanisms by which drugs permeate the stratum corneum are still under debate but there is substantial evidence that the route of permeation is a tortuous one following the intercellular channels. The diffusion path length is between 300 and 500 μm rather than the 20 μm suggested by the thickness of the stratum corneum [16]. The intercellular channels contain a complex milieu of lipids that are structured into ordered belayed arrays [17]. A diffusing drug has to cross, sequentially, repeated bilayers and therefore encounter a series of lipophilic and hydrophilic domains. The physicochemical properties of permeant are therefore crucial in dictating the overall rate of delivery [18]. A molecule that is hydrophilic in nature will be held back by the lipophilic acyl chains of the lipids and conversely, a lipophilic permeant will not penetrate well through the hydrophilic head-group regions of the lipids.

Transdermal delivery system of antidiabetic drug like glipizide has already been marketed. The impermeability of the skin has led to the development of a number of enhancement strategies.

Antidiabetic drugs:

1. Glipizide:

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy the rationale of this study was to develop a transdermal delivery system for glipizide [10]. Glipizide is a potent, second generation oral sulphonylurea drug. Being a weak acid (pka=5.9), glipizide is better absorbed from acidic medium; however, at very low pH levels, the solubility of glipizide is minimal [12]. Even though on the weight basis it is approximately 100 times more potent then tolbutamide, the maximal hypoglycaemic effect of these two agents are similar. It is rapidly absorbed on oral administration, with a serum half life of 2 to 4 hours, while the hypoglycaemia effect range from 12 to 24 hours [19].

Ammar HO et al. [10] formulated transdermal formulation of the drug in carbopol base containing 20% propylene glycol together with 15% oleic acid and formulation containing glipizide - cyclodextrin complex in presence of 15% urea showed best biological performance, as evidenced by: an intensity of action comparable with the orally administered drug; a significant increase in duration of action extending up to 48 h; a significant increase in bioavailability as depicted from the values of the area under percentage decrease in BGL versus time curve (AUC: 0-48h) which is significantly higher than that of the orally administered drug.

2. Gliclazide:

Gliclazide, a second-generation hypoglycaemic agent, faces problems like its poor solubility, poor oral bioavailability with large individual variation and extensive metabolism. It is very similar to the tolbutamide with the exception of the bio-cyclic heterocyclic ring found in gliclazide. The pyrrolidine increases its lipophilicity over that of tolbutamide, which increases its half life even so the p-methyl is susceptible to the same oxidative metabolic fat as observe for tolbutamide namely it will be metabolized to carboxylic acid [19].

Kumar A et al. [3] formulated transdermal matrix-type patches by film casting techniques on mercury using polymers like HPMC, Eudragit RL-100, and chitosan. Also an attempt was made to increase the permeation rate of drug by preparing an inclusion complex with hydroxypropyl β-cyclodextrin (HP β-CD). The possibility of a synergistic effect of chemical penetration enhancers (CPE) (propylene glycol and oleic acid) on the transdermal transport of the drug was also studied. Folding endurance was found to be high in patches containing higher amount of the eudragit. There was increase in tensile strength with an increase in eudragit in the polymer blend. The patches containing inclusion complex of drug showed higher permeation flux compared with patches containing plain drug.

3. Gliquidone:

Gliquidone, a second generation sulfonylurea has been investigated for transdermal delivery.

Sridevi S et al. [8] studied that the poor aqueous solubility of the drug prompted the use of hydroxypropyl-beta-cyclodextrin (HP β-CD), a cyclic oligosaccharide, which is known to facilitate transdermal permeation of many drugs by enhancing the solubility and thus improving the diffusible species of the drug molecules at the skin-vehicle interface. In order to optimize the transdermal delivery of gliquidone, the effect of pH along with complexation on the solubility and permeation has been investigated. The solubility profiles of the drug, on increasing the concentration of HP β-CD were of higuchi's AL type at the three pH values evaluated. However, the solubilisation slope of the drug at pH 7.0 was 22 times that at pH 3.0 as a result of greater intrinsic solubility of the ionized form of the drug at pH 7.0. Transdermal flux of gliquidone at pH 7.0 was significantly greater than the flux at pH 3.0 in the presence of 15% w/v HP β-CD, attributable to the better solubility of the drug at pH 7.0 in the presence of HP β-CD. The effect of increasing concentrations of HP β-CD investigated at variable drug loading in the donor phase at pH 7.4 endorsed the earlier observations from studies on other drugs that the drug has to be present at saturation in HP β-CD aqueous vehicle to achieve an optimized flux. While at saturation, the steady state flux of gliquidone from the aqueous HP β-CD (25% w/v) vehicle was enhanced 31 times compared to pure drug suspension at pH 7.4, unsaturation in the donor phase resulted in the decreased flux of gliquidone. It was concluded from the present study that enhanced transdermal flux of gliquidone can be achieved by adjusting the pH and the concentration of HP β-CD to achieve a better solubility of the drug.

4. Glimepiride:

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. Glimepiride therapy improves postprandial insulin/C-peptide response, and overall glycaemia control. The problem arrived by the oral glimepiride therapy upon the bioavailability due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the transdermal delivery system for glimepiride was being developed.

Ammar HO et al. [11] formulated chitosan films for transdermal delivery of glimepiride. He used chitosan due to its film forming ability, bioadhesive and absorption enhancing properties. He formulated three formulations as chitosan films containing glimepiride, the same formula in presence of a combination of 5% limonene together with 10% ethanol and chitosan film comprising glimepiride - cyclodextrin complex. In addition, a plain chitosan film of the same size was also examined concurrently. The hypoglycaemic effect of the selected formulations was assessed in diabetic rats and compared to oral administration of the drug. The study revealed that the percent drug released from the chitosan film comprising glimepiride and that comprising glimepiride – cyclodextrin complex were adequate, reaching 39.68 ± 1.73 and 61.50 ± 2.02 within 6 hours, respectively (mean ± S.E., n = 3). The release rate values revealed that complexation of the drug within cyclodextrin leads to significant enhancement (p<0.005) of the release rate from 0.185 ± 0.007 (mg cm^-2h^-1) to 0.242 ± 0.008 (mg cm^-2 h^-1).

Transdermal glimepiride will helped to maintain good glycaemia control for relatively prolonged period of time and, in turn, help to prevent long term complications.

5. Glibenclamide [20]:

Glibenclamide is an anti-diabetic drug in a class of medications known as sulfonylureas. It is also sold in combination with metformin under the trade name Glucovance.

Glibenclamide exerts pancreatic and extrapancreatic actions. It stimulates an increase in insulin release by the pancreatic β-cells. It may also reduce hepatic gluconeogenesis and glycogenolysis. Increased glucose uptake in the liver and utilization in the skeletal muscles.

Sharma A et al. [21] formulated matrix-type transdermal patches in which the drug embedded in a polymeric matrix of polymethyl methacrylate and ethyl cellulose was evaluated for its hypoglycaemic activity in normal and streptozotocin induced diabetic rats in comparison with its oral therapy.

6 Metformin:

Metformin hydrochloride, an oral anti-diabetic drug frequently used as first line drug of choice in treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function [22]. Metformin is anti-hyperglycaemic and it does not cause insulin release in the pancreas. Metformin reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fat. Metformin is absorbed mainly from the small intestine and does not bind to plasma proteins [23].

Obstacle to more successful use of metformin hydrochloride therapy is the high incidence of gastrointestinal side effects and rapid first pass metabolism. These problems can be overcome by the preparation of transdermal patches of metformin hydrochloride.

Allena RT et al. [24] developed a sustained release transdermal patch of metformin hydrochloride using a natural polymer like chitosan and a hydrophilic polymer like HPMC. Release kinetic studies revealed that the drug release from formulation followed zero order kinetics with release exponent value n=0.966, which shows that release pattern of patches follows non-fickian diffusion mechanism. It was observed that the system with chitosan: HPMC in the ratio 5:1 along with plasticiser was very promising in controlling release of metformin via transdermal drug delivery system.

6. Rosiglitazone:

Rosiglitazone maleate, belonging to the class of thiazolidinedione, is an oral anti-diabetic drug, which is particularly suitable for diabetic patients who are overweight and for whom metformin is contraindicated [25, 26]. It improves the glycaemia control primarily by increasing peripheral insulin resistance and sensitizing the skeletal muscle, liver and adipose tissue to the actions of insulin, in addition to improving beta-cell function [27].

Ghosh B. et al. [28] delivered rosiglitazone maleate from hydro-alcoholic vehicle of different composition and in vitro skin permeability through full thickness ear skin of domestic pigs (Sus domesticus) was observed in a Franz-diffusion cell using 0.9% NaCl as the receptor fluid. For iontophoretic diffusion, a current density of 0.5 mA/cm² was used. Permeation rate of rosiglitazone maleate had increased with increase in donor drug concentration (p<0.01) up to the level of 213.71 μmol/ml in both passive diffusion and iontophoresis resulting in good skin permeability.

CONCLUSION:

The brief overview of the different antidiabetic drugs revealed that, by delivering through the transdermal route improves bioavailability as well improve the patient compliance by many fold. But the demerit is that, all the antidiabetic drugs cannot be given as transdermal delivery because the drug should have specific physicochemical property which should be suited to permeate through skin. The development of success transdermal drug delivery system depends on proper selection of drug, polymer as well as other additives

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Received on 21.05.2013

Modified on 22.06.2013

Accepted on 10.08.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(5): September-October, 2013, 252-256