An Introduction To Diabetes Mellitus

Diabetes mellitus was recognized as early as 1500 B.C. by Egyptian Physicians, who described it as a disease associated with “the passage of much urine”. The term “diabetes” (the Greek for Siphon) was coined by the Greek Physician Aretaeus the Cappadocian around A.D.2. In 1674 a physician named Willis coined the term “Diabetes Mellitus” (from the Greek word for Honey).1, 2

Diabetes mellitus is a complex syndrome that affects multiple organ systems. It is now clear that diabetes is a heterogeneous group of disorders that are elicited secondary to various genetic predispositions and precipitating factors.3

Diabetes mellitus is a chronic disease that is characterized by disorders in carbohydrate, protein and lipid metabolism. Its central disturbance appears to involve an abnormality either in the secretion of or effects produced by insulin although other factors also may be involved.4 Diabetes mellitus is a metabolic disorder in which carbohydrate metabolism is reduced while that of proteins and lipids is increased.5

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The external secretion of the pancreas is digestive in function and the intestinal secretions play a major role in the regulation of metabolism. The hormones which regulate the level of blood sugar are mainly two; glucagon from the alpha-cells and insulin from the beta-cells of the islets of langerhans.6

Glipizide is 200 times more potent than tolbutamide in evoking pancreatic secretion of insulin. It differs from other oral hypoglycemic drugs where in tolerance to this action apparently does not occur.9 It also upregulates insulin receptors in the periphery, which seems to be the primary action. It has a special status in the treatment of non-insulin-dependent diabetes mellitus because it is effective in many cases which are resistant to all other oral hypoglycemic drugs. It differs from other oral hypoglycemic drugs ie more effective during eating than during fasting.

Over the year controlled drug delivery technology has a wide advances. Due to its high potential a bioadhesive system place a major role in controlling drug release. Mucoadhesive system prolong the residence time of the dosage form at the site of application or absorption and facilitate an therapeutic performance of the drug. Recent interest has been expressed in the delivery of drug via mucus membrane by the use of adhesive materials on which studies are been intensively undertaken.58

Glipizide is an oral antidiabetic drug, belonging to the sulphonylurea group. Presently the drug is marketed in conventional dosage form of tablet in usual strength of 2.5 to 20 mg. When the drug is administered by this route, about 50% of drug is metabolized in the liver to the several inactive metabolites. Hence there is need of the alternative route administration to avoid first pass hepatic metabolism.7 More over the combination of anti-diabetic drugs with NSAIDS are not available in market.

Physicochemical properties of this drug like small dose, lipophilicity, stability at buccal pH, odourlessness, tastelessness, low molecular weight etc. makes it an ideal candidate for administration by buccal route.

For hydrophilic substances, the rate of absorption is a function of the molecular size. Small molecules (<75-100 Da.) appear to cross the mucosa rapidly, but permeability falls off rapidly as molecular size increases. Since permeability has been observed to decrease sharply as molar volume is increased beyond 80ml/mol, investigators have proposed — two distinct polar routes. This relationship between size and permeability has not been demonstrated for lipophilic substances, although common sense suggests that such a relationship must exist.

The degree of ionization of a permeant is a function of both its pka and the pH at the mucosal surface. For many weak acids and weak bases, only the unionized form possesses appreciable lipid solubility. The absorption of many compounds has been shown to be maximal at the pH at which they are mostly unionized, tailing off as the degree of ionization increases. Other studies, however, have failed to show this pattern.

In common with drug transport across other epithelia, there are a number of possible permeation pathways across the oral mucosae. The classical distinction is between transcellular and paracellular permeation, referring to passage across the individual cells of the epithelium and passage between these cells, respectively. For transcellular permeation, the permeant must be capable of passing through pores in the cell membranes or diffusing through the lipid bi-layers of these membranes. Passage through membrane pore would probably be limited to small molecules, while diffusion across cell membranes would require appreciable aqueous and lipid solubilities. Paracelluler permeation requires the epithelium to have a sufficiently open matrix and requires the permeant to have an appreciable diffusivity in the intercellular milieu. It seems likely that large and/or highly polar permeants may be unable to pass through the epithelial cell membranes and might, therefore, follow the paracellular route.

An alternative classification is into polar and non-polar routes, the former involving passage of water-soluble substances through aqueous channels in the mucosa and the latter involving partitioning of the drug into the lipid bilayer of the plasma membrane or into the lipid of the intercellular matrix and diffusion through these lipid elements.

Almost all studies have shown that, for most permeants passage across the oral mucosae appears to be a first-order simple diffusion process. It has also been suggested, however that the oral mucosae contain active or carrier-mediated systems for small molecules such as monosaccharides and amino acids. However, these processes have not been fully characterized in terms of location, transport capacity or specificity.

The kinetics of oral mucosal absorption have been studied by a number of workers. Some investigations have shown a slow onset of appearance of permeant in the systemic circulation and a depot-like behaviour of the oral mucosae which have been attributed to some form of binding within the mucosae. To date, however, this area has not been systematically investigated and remains for the most part poorly understood.

Possible routes for drug transport across the oral mucosa: 16

The cellular structure of the oral mucosa suggests that there are two permeability barriers. The intercellular spaces and cytoplasm are essentially hydrophilic in character and become a transport barrier for lipophilic compounds mainly because the solubility of lipophilic compound in this environment is low. In contrast, the cell membrane is lipophilic and the penetration of a hydrophilic compound into the cell membrane is low due to a low partition coefficient. Thus, closely compacted cell membranes become obstacles that hydrophilic compounds have to move around.

The coexistence of the hydrophilic and lipophilic regions in the oral mucosa suggests that there are two routes for drug transport, i.e., the paracellular and the transcellular routes (Diag.3).

PERMEATION ENHANCEMENT: 14, 15

While the sublingual mucosa is sufficiently permeable to allow the therapeutic delivery of a number of small drug molecules, low mucosal permeability is perceived to be a significant obstacle to buccal delivery.

Permeation enhancers are substances added to a pharmaceutical formulation in order to increase the membrane permeation rate or absorption rate of a co-administered drug.

Attention is thus focused on some of the strategies that have been proposed for enhancing the permeability of the oral mucosae. A considerable number of agents have been proposed as penetration enhancers. The agents used have mostly been small hydrophilic molecules. E.g., dimethyl sulphoxide, dimethyl formamide, ethanol, propylene glycol, and the 2-pyrrolidones, long-chain amphiphathic molecules (decylmethyl sulphoxide, azone, sodium lauryl sulphate, oleic acid and the bile salts), and non-toxic surfactants (polysorbates). Although some are effective, either alone or in combination, their modes of action are not fully understood.