ORAL DRUG DELIVERY OF INSULIN IN DIABETES MELLITUS: AN ATTRACTIVE ALTERNATE TO OVERCOME INVASIVE ROUTE

The subcutaneous injection of insulin for the treatment of diabetes mellitus can lead to patient non-compliance, Diabetes discomfort, pain and local infection is a chronic metabolic health disease affecting the homeostasis of blood sugar levels in human beings. Oral route of drug delivery system has been the most widely accepted means of drug administration for formulating other than invasive drug delivery systems. For the development of an oral insulin delivery system, we have to focus on defeating various gastro-intestinal barriers for insulin uptake across the gastrointestinal tract. To defeat these barriers various types of formulations such as insulin conjugates, micro/nanoparticles, liposomes, hydrogel, capsule, and tablets are designed to deliver insulin orally. Various potential ways to administer insulin orally has been explored over years but a fluctuating level of success. A number of advancement has taken place in the recent years for understanding the needs of improved oral delivery systems of insulin. This review article concentrates on the challenges for oral drug delivery of insulin as well as various carriers used for the oral drug delivery of insulin and also provides the relevant information about the clinical tested formulations of oral insulin and its patents.


INTRODUCTION
The effective treatment of diabetic person with insulin need painful route of administration. Although invasive routes are poorly acceptable by the diabetics but other noninvasive routes of administrations are highly expedient 1 . Administration of drugs by oral route is the most acceptable route of administration, but it is difficult to deliver peptide and protein drugs by this route. Presystemic enzymatic degradation and poor penetration of the intestinal membrane are the main reasons for the low oral bioavailability of peptide and protein drugs 2 . Oral bioavailability of insulin is below 1% so there is a big challenge to improve it upto 30%-50% 3 . A number of polymers both biodegradable and non-biodegradablepolymers have been studied for non-invasive delivery of insulin. Nonbiodegradable polymers possess problems of toxicity, difficulty in eviction and also sustained release of insulin cannot be attained using these polymers. Biodegradable polymers favour the uptake of insulin through intestinal cells by shielding the encapsulated drug from the external harsh conditions. Biodegradable polymeric particles protect the peptide from the peptidases, so that they can be uptake by enterocytes. Polymeric particles will slowly degrade after absorption depending on the nature of the polymer; provide a sustained and controlled release of the drug 4 .Various strategies have to be implemented to maximize oral insulin bioavailability to defeat GI barriers, and to bring safe and effective oral dosage form to the market 5 . In order to attain an ideal oral peptide drug delivery system, some alternates will be required to encapsulate the insulin 6 .For the oral delivery of peptide and protein drugs, nanocarriers have shown great potential withimproved pharmacokinetics and pharmacodynamics of insulin. Nanocarriers or nanoparticlescan stabilize these macromolecular drugs by providing insulation from the harsh GI conditions and accelerating their transport across the absorptive epithelia 7 . The new strategies for products that are tried before include water-soluble, long-acting insulin derivative, [(2-Sulfo)-9-fluorenylmethoxycarbonyl]3-insulin, vitamin B12-dextran nano particles, lipid nano particles and PEGylated calcium phosphate nanoparticles etc as oral drug delivery carriers for insulin 8 .

VARIOUS CHALLENGES TO ORAL INSULIN DRUG DELIVERY Absorption across GIT membrane
General route for absorption of drug molecules is the Paracellular and the transcellular route. Hydrophilic molecules having mol. Wt. less than 500 Da absorbed by Paracellular route. The molecules having high molecular weight like insulin (about 6KDa) cannot absorb via this route. Absorption of insulin by transcellular route is restricted because of its molecular size, its charge, and its hydrophilicity 9 . To increase the GI uptake of orally poorly absorbed insulin is their binding to colloidal particles that can safeguard the insulin from degradation in the GI tract and encourage the transport of poor-absorbable molecules into systemic circulation 10 .

Presystemic enzymatic degradation
Pepsin is present inside the stomach as a group of aspartic proteases. Pancreatic proteases existing in small intestine comprising the serine endopeptidase (trypsin, α-chymotrypsin, elastase and exopeptidases, carboxypeptidase A, and carboxypeptidase B) which is accountable for the degradation of proteins.The order of enzymatic degradation of insulin in the small intestineis Duodenum> jejunum > ileum 9 .Insulin can be available for absorption through GIT when the enzymatic attack is either diminished or defeated 11 .Although Insulin is not subject to proteolytic breakdown by brush border enzymes 12 .

Poor Intestinal transport of insulin
The anatomy of insulin is very exquisite. Insulin is susceptible to oxidative damage when react amino acids 9 . In other terms we can say that insulin has low permeability via intestinal mucosa 11 . Dosage form stability Proteins changesits conformation, size, shape, surface properties, and bioactivity upon development into different formulations. Changes in conformation, size, shape can be detected by use of spectrophotometric techniques, X-ray diffraction, differential scanning calorimetery, light scattering, electrophoresis, and gel filtration 12 . (Figure 1)

FEATURES OF AN ABSOLUTEORAL INSULIN CARRIER
An absolute carrier for insulin: ■ should be pH sensitive. ■ should provide a biocompatible and stable environment to ensure that the active part of insulin will remain biologically active after encapsulation. ■ should reduce or avoid enzyme degradation and increase insulin permeability across the intestinal membrane. ■ thepermeability of the mucosal epithelium to enhance the absorption ofinsulin and provide the intact insulin to the blood circulation. ■ must be safe after oral administration. ■ Insulin should be available for interaction with cell surface receptors and captured by lymphatic cells, or pass through or be entrapped in thelymph nodes or transferred to the systemic circulation, provided that the particles remain as such and particle size will be acceptable up to a limit 13 .

DIVERSE CARRIERS USED FOR NON INVASIVE DRUG DELIVERY OF INSULIN Insulin-loaded Bioadhesive PLGA Nanoparticles for Oral Drug Delivery
PEGylation play an important role in increasing the stability of several therapeutic proteins 14 .For the drug delivery system of proteins and peptides Poly (D, L-lactide-co-glycolide) nanoparticles (PLGA-NP) have been used extensively. Chitosan PLGA nanoparticle hassome attractive properties, such as a mucosal adhesion, positive charge, and absorption enhancement, which increase the duration of residence of insulin in in-vitro and improve its bioavailability in in-vivo for oral delivery 15 .The negative surface charge present on PLGA nanoparticles tends to reduce the oral bioavailability bylimiting the diffusion of insulin nanoparticle across the mucus layer. Cationic chitosan can be used tocoat and modify the surface charge of PLGA nanoparticles 16 .

Polymeric Hydrogels for Oral Insulin Delivery
Nature of the polymer might enhance the residence time of a drug delivery system inside the GI tract 17 .Polymerichydrogels protect insulin from enzymatic degradation in acidic environment of stomach and deliversinsulin effectively in the intestinal region. Swelling andde-swelling mechanisms of the hydrogel under differentpH conditions of the body control the release of insulin. A Combination of enzyme inhibitors and polymeric systems have potentialto increase the potency of orally given insulin 15 .

Acrylic Polymers for Oral Insulin Delivery
Acrylic polymers are synthetic mucoadhesive polymers, basically intended for oral drug delivery. Various technique used to generate Synthetic polymers areNano precipitation, solvent evaporation, freeze-drying, spray drying of emulsions and supercritical fluid technology 15 . Methacrylic acid or acrylic acid are used as copolymerfor their pH-sensitive nature and ability to bind calcium, and poly (ethylene glycol) because of its ability to stabilize and protect proteins 18 .

Aerosolized Liposomes for Pulmonary Delivery of Insulin
Pulmonary route for systemic delivery of peptides and proteins is paid more attention because it's a non-invasive method of administrating insulin and hence valuable for the delivery of large molecular proteins 14 .This method is effective for both type 1(T1DM) and type 2 diabetes mellitus(T2DM) 19 . Generally lungs have large surface area (approximate about 100 square metres) and acts as an ideal target for insulin delivery 20 .

Chitosan-zinc-insulin Complex
Chitosan, a biodegradable polymer and a cationic polysaccharide, has been extensively known for the preparation of nanoparticles for oral controlled delivery. Chitosan derivatization of polymers that improve drug retention capability, provideimproved permeation, enhanced mucoadhesion and sustained release of therapeutic agents 8 .

MARKET STATUS OF ORAL INSULIN FORMULATIONS
In the recent years, the oral dosage form development of insulin is at different clinical stages frompre-clinical testing to Phase II clinical trials 21 . Oralin has been successfully trailed in Type 1 and Type 2 diabetic patients and when the results were compare with subcutaneous injectionit was find appropriate for controlling blood glucose level 22 . A remarkable progress has been reported in the recent past years for the delivery of insulin by non-invasive routes. Some of other hormonal drugs, such as calcitonin and vasopressin, are available in the form of intranasal sprays. The field of oral insulin delivery took an enormous step ahead with the approval of Exubera® from Pfizer and Nektar Therapeutics 5 . (Table 1) CONCLUSION An extensive number of peopleespecially in developed countries are suffered from diabetes. The pharmacotherapy for T1DM and T2DM treatment is subcutaneous injection of insulin. Discomfort, pain and local infection are themain reasons for patient non-compliance. On the otherhand, if we develop oral dosage form of insulin formulation then we can improve patient acceptability. Painful administration and phobia from invasive routes have couragescientists to research new possible methods for oral insulin delivery. Various barriers to insulin uptake by oral routes has its own set of advantages and disadvantages. Over the last few years, researchers have focused on oral insulin delivery. Although extensive human clinical studies are still the major requirement of oral insulin drug delivery and for theoptimisation of physiochemical and pharmacokinetic parameters of insulin as drug carrier for diabetes treatment.