INTRODUCTION

Insulin therapy is effective at lowering blood glucose in patients with diabetes [diabetes mellitus (DM)]. Insulin is a key player in the control of hyperglycemia for type 1diabetes patients while it is required at later stage or in selective individuals in patients of type 2 diabetes. The discovery of insulin was considered as one of the most dramatic events in the history of the treatment of diabetes. It was isolated in 1921 with its first clinical use in1922. The major advances achieved in this area include the synthesis of human insulin analogues by recombinant technology.

Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The ultimate goal would be to eliminate the need to deliver insulin exogenously and regain the ability of patients to produce and use their own insulin. The major drawback of current forms of insulin therapy is their invasive nature. In type 1 diabetes, good glycemic control usually requires at least three or more daily insulin injections. To decrease the suffering and improve the adherence in insulin regimens, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. The search for more acceptable methods for administering insulin continues. Several on-invasive approaches for insulin delivery are being pursued. The success of the route of administration is measured by its ability to elicit effective and predictable lowering of blood glucose level and minimizing the risk of diabetic complications. The newer methods explored include the artificial pancreas with closed- loop system, transdermal insulin, and buccal, oral, pulmonary, nasal, ocular and rectal routes. This review focuses on the new concepts that are being explored for use in future.(Yaturu 2013)

PREVALANCE STUDY:

The prevalence of diabetes is increasing throughout the world. The International Diabetes Federation estimated 366 million people had diabetes in 2011 and is expected rise to 552 million by 2030. Though type 2 diabetes mellitus (T2DM) accounts for 85-95% of diabetes, the prevalence of T1DM has increased by 2-3% in certain parts of Europe and USA. Thus, diabetes has become one of the most common noncommunicable diseases worldwide.(Garg, Michels et al. 2013).

Discovery of insulin was one of the greatest medical discoveries of the last century. All patients with T1DM and many patients with long standing T2DM require insulin therapy to achieve good glycemic control. The early insulins were derived from bovine and porcine pancreas and were associated with immunological reactions, lipodystrophy and unpredictable insulin absorption from subcutaneous tissue. Hence, initial research focused on the purification of insulin. There has been marked progression in the development of insulins such as rapid and long acting insulin analogs in the last five decades.(Group 1995)

INSULIN DELIVERY METHODS:

Insulin can be administered subcutaneously via various methods such as vial and syringe, insulin pen and continuous subcutaneous insulin infusion (CSII) Fig.1 (Rima B. Shah1 2016)

CURRENT METHODS IN INSULIN THERAPY:

Vial and syringe:

The word syringe came from the Greek “syrinx,” which means “tube.” The development of syringes dates back to 1853. One of the earliest syringes was the Fergusson syringe that paved the way for the development of the modern syringes. The intravenous route was the first parenteral route for drug delivery reported through syringes and needles in the late 17th century, and the subcutaneous route of drug delivery was established in the early 19th century. In 1924, 2 years after the discovery of insulin, Becton, Dickinson and Company (BD) made a syringe specifically designed for the insulin injection. Initial syringes were made of metals and/or glass, were reusable and required boiling after each use to sterilize. To reduce the incidence of needle associated infections, disposable syringes were developed. BD mass produced the first glass disposable syringes in 1954, called the BD Hypak. A number of modifications have been made to the modern insulin syringes and needles over the last five decades. Despite all these advances, many patients do not feel to inject insulin 3-4 times a day as a result of needle phobia. Recently, an injection port has been designed know as i-port Advance. It is the first device to combine an injection port and an inserter in one complete set that eliminates the need for multiple injections without having to puncture the skin for each dose. This device is helpful for the insulin requiring patients having needle phobia and helps them to achieve glycemic control effectively.(Burdick, Cooper et al. 2009, Fry 2012)

Insulin Pens:

Insulin pens more discreet compared with vials and syringes. Insulin pens combine the insulin container and the syringe into a single modular unit. Insulin pens eliminate the inconvenience of carrying insulin vials and syringes and are more accurate and less painful. Insulin pens are user-friendly, with decreased discomfort of injection, ease of cartridge replacement, insulin-dose setting dial use and prominence of audible clicks can all affect overall dose accuracy. These are the advantages over syringes and needles. Reusable insulin pens offer a wide range of advantages such as their durability, eliminating the need for cartridge refrigeration and providing flexibility in carrying a three to five day supply. Patient satisfaction and preference is higher with pen use compared to syringes and needles. Resistance to initiation of insulin use by many patients and some clinicians is due to concerns about its complexity or a general resistance to injections. Effective glycemic control remains an important clinical goal. Patient barriers to accepting insulin initiation with current delivery systems include fear of hypoglycemia, fear of injections, possible weight gain, and reluctance to accommodate the inflexible timing of scheduled insulin doses. Adherence issues, including dose omission, are common and are associated with some of the same factors. In addition, the invasive nature of the syringe, pump, and pen remains an obstacle for patients.(Penfornis, Personeni et al. 2011, Shah, Patel et al. 2016)

Continuous subcutaneous insulin infusion:

More physiologic delivery of insulin has been a long-standing goal. In normal physiology, a continuous small amount of insulin secretion from the beta cells of the pancreas reduces hepatic glucose output, and a larger amount of insulin is secreted when food is ingested to maintain euglycemia. Although multiple daily injections (MDI) therapy can effectively achieve hemoglobin A1c (A1c) goals, it does not resemble the insulin secretion from pancreatic beta cells. Hence, it is associated with high glycemic variability (i.e., hypoglycemia and hyperglycemia).

The first portable insulin pump was invented by Kadish in 1963; however, it was limited efficient and comfortable to the patient. The first commercial insulin pump was introduced in 1979 in the USA. The DCCT trial used CSII therapy in nearly 40% of the intensive arm. The current generation of insulin pumps are more patient friendly as a result of smaller size and smart features such as built-in-dose calculators and alarms.

Clinical trials have demonstrated the effectiveness of CSII over MDI therapy in achieving glycemic goals (~0.5% A1c reduction), reduction in insulin dosage (~14%), reduction of hypoglycemia and glycemic variability and improved patient satisfaction and quality of life. Limitations of CSII therapy include: Higher cost compared with MDI, increased risk for subcutaneous infections, inconvenience of being attached to a device, and a theoretical higher risk for diabetic ketoacidosis. Patient education before starting CSII therapy is of utmost important to avoid these complications.

Sensor-augmented pump therapy:

With the improvements in continuous glucose monitors (CGM), it has become feasible to combine two technologies (pump and CGM) in the management of diabetes. The new generations of CGMs are more accurate, smaller in size and shown to improve glycemic control in patients with T1DM. When CGM readings are used to adjust insulin delivery through insulin pump, it is known as sensor-augmented pump (SAP) therapy. The use of SAP reduces A1c by 0.7-0.8% compared to baseline or MDI therapy in patients with T1DM. SAP requires patient involvement for using CGM glucose readings to adjust insulin pump delivery. This makes SAP susceptible to human errors. In addition, SAP therapy requires patients to wake up to manage nocturnal hypoglycemia.(Cohen, Körner et al. 2009)

Sensor-augmented pump with low glucose suspend or threshold suspend pump:

Hypoglycemia is the most feared acute complication of insulin therapy in patients with T1DM. More than half of hypoglycemia occurs during the night and although rare, 6% of deaths are due to nocturnal hypoglycemia in younger individuals with T1DM. In addition, the MDI, CSII and SAP are not able to eliminate nocturnal hypoglycemia. Therefore, the first step in making an artificial pancreas (closed-loop system) is to suspend insulin delivery once CGM glucose is at a low threshold (often 70 or 60 mg/dl) to reduce nocturnal hypoglycemia.

The threshold suspends (TS) system suspends the delivery of insulin for up to 2 h if a patient does not take action with a low glucose alarm. This feature is designed to reduce the severity and duration of hypoglycemia, although it will not prevent hypoglycemia. 2h of insulin suspension is not associated with severe hyperglycemia and/or diabetic ketoacidosis or more likelihood of ketone. In clinical trials, TS reduced the severity of nocturnal hypoglycemia by 30-40% and reduced the duration of severe hypoglycemia without altering A1c values. Recently, the TS system has been approved by US Food and Drug Administration (FDA) after having been approved in 2009 in other countries.

Future steps in the evolution of the artificial pancreas will be(Shah, Shoskes et al. 2014)

(1) Use of predictive algorithms to minimize hypoglycemia even before hypoglycemia occurs.

(2) Use of algorithms to keep blood sugar in target range (hypoglycemia/hyperglycemia minimizer).

(3) Automated basal and/or hybrid close-loop and

(4) Fully automated the single (insulin) or

(5) Dual (insulin + glucagon) hormonal close-loop.

FUTURE TRENDS:

Newer injectable insulins:

Newer insulins that are promising include long acting basal insulin analogue called insulin degludec and ultra fast acting insulin, human insulin Linjeta™ (formally called VIAject).

Insulin degludec:

Insulin degludec, novel ultra-long acting basal insulin, is almost identical to human insulin in structure except for the last amino acid deleted from the B-chain and addition of a glutamyl link from LysB29 to a hexadecandioic fatty acid. This insulin forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile with half life more than 24 h. Insulin degludec has proven to be non inferior to insulin glargine in clinical trials carried out in both type 1 and type 2 DM. Exploratory studies in type 1 diabetes have shown insulin gegludec to be safe with reduced rates of hypoglycemia and comparable glycemic control to long acting insulin analogue insulin glargine. Phase 3 clinical trials in adults with type 1 DM and type 2 DM glycemic controls was comparable to insulin glargine at one year follow up with fewer hypoglycemic episodes. As insulin degludec has an ultra-long acting profile, insulin degludec was studied using injections three times a week compared with insulin glargine once a day and found to have comparable response. The advantages of insulin degludec were reviewed in several recent publications. Comparative studies of efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin as part, in basal-bolus therapy for type 1diabetes and type 2 diabetes noted effective glycaemic control with a lower risk of nocturnal hypoglycemia than insulin glargine. Similar studies comparing insulin degludec along with as part insulin compared to insulin detemir with aspart insulin noted improved overall glycemic control while lowering the risk of nocturnal hypoglycemia and fewer injections. Insulin degludec is not yet approved by Food and Drug Administration.(3)

VIAject™: VIAject is recombinant human insulin with ultra fast onset of action. Pharmaco-dynamic and pharmacokinetic studies have shown the onset of action of VIAject is faster than that of human soluble insulin and insulin lispro. VIAject was reported to have less with in subject variability of plasma insulin compared to human regular insulin, and has a faster absorption/onset of action than insulin lispro. Two pivotal phases clinical studies in both type 1 and type 2 DM are ongoing with VIAject. As the amount of insulin circulating several hours after a meal is low, a possible reduction in hypoglycemia and prevention of weight gain are predicted.(3)

NOVEL APPROACHES TO DELIVER INSULIN:

The subcutaneous route of insulin administration is associated with many drawbacks such as injection pain, inconvenience, variable compliance and difficulty in achieving postprandial blood glucose control. In addition, subcutaneous insulin administration results in peripheral hyperinsulinemia in contrast to physiologic delivery to the portal vein. Therefore, there is interest in delivering insulin by alternate noninvasive routes. Currently, the pulmonary route of administration is approved and discussed as well as other routes under investigation.(4)

ARTIFICIAL PANCREAS:

Introduction of continuous glucose sensors has led to development of the artificial pancreas, which made improved care possible. Even with the use of continuous glucose monitors and insulin pumps, most people with type 1 DM do not achieve glycemic goals and continue to have unacceptable rates of hypoglycemia. Closed-loop insulin delivery, also referred to as the artificial pancreas, is an emerging therapeutic approach for people with type 1 DM. In this closed-loop, blood glucose control is achieved using an algorithm, wireless communication of a continuous glucose monitor linked to insulin infusion pump that facilitates automated data transfer and delivers insulin, without the need for human intervention.

The goal of closed-loop therapy is to achieve good glycemic control with the use of a control algorithm that directs insulin delivery according to glucose levels while reducing the risk of hypoglycemia. Beta cells respond to circulating glucose levels by feedback mechanism. Insulin delivery in the closed loop system is modulated at intervals of 1 to 15 min, depending on interstitial glucose levels. The novelty of this approach resides in the real-time feedback between glucose levels and insulin delivery, similar to that of the beta-cell.

The algorithms that are most relevant of the available various algorithms include the proportional-integral derivative control and the model-predictive control. True closed-loop systems, that determine minute-to minute insulin delivery based on continuous glucose sensor data in real-time, have shown promise in small inpatient feasibility studies, using a variety of algorithmic and hormonal approaches. To have a near normal closed-loop system, several areas need to be improved. First and foremost is the rapid onset of action. Lag period of current fast acting insulin analogs is 90-120 min.

The limitations of current glucose sensors include a lag period, as they measure interstial fluid rather than blood glucose, and errors from transient loss of sensitivity. Rapid acting insulin are being developed. Addition of recombinant human hyaluronidase (rHuPH20) accelerates insulin absorption. Current trials show promise. Both lispro and recombitant human insulin with rHuPH20 in phase 2 studies noted earlier and greater peak insulin concentrations and improved postprandial glycemic control and reduced hypoglycemia.

Use of monomeric insulins that cannot form hexamers are being developed. As mentioned earlier, ultrafast insulin VIAject, a formulation of human soluble insulin improves the rate of insulin absorption. Steiner and associates have reported that VIAject has higher metabolic activity in the first 2 h after injection as noted in their study to evaluate the pharmacodynamic and pharmacokinetic properties.(3)

INHALED INSULIN:

Insulin delivery to the lungs was the first reported alternate to subcutaneous injection. It has long been appreciated that insulin delivery by aerosol reduces blood glucose. Early studies showed that delivering bovine or porcine insulin using a nebulizer produced a prompt hypoglycemia in subjects with and without diabetes.

Advantages of the pulmonary route include a vast and well perfused absorptive surface, absence of certain peptidases that are present in the gastrointestinal (GI) tract that breaks down insulin, and the ability to bypass the “first pass metabolism. However, the exact mechanism of insulin absorption across the pulmonary epithelium remains unclear, but it is believed to involve transcytotic and paracellular mechanisms.

The first inhaled product, Exubera^® was approved by the US FDA in year 2006. Exubera^® was a dry power formulation available as 1 mg and 3 mg doses to be taken with the help of an Inhance™ inhaler device. Exubera^® was found to have pharmacokinetic and pharmacodynamic (PK/PD) properties similar to insulin as part with a faster onset of action (10-15 min). In clinical trials in patients with uncontrolled T1DM and T2DM, Exubera^® was found to reduce postprandial blood glucose and A1c significantly. However, Exubera^® was contraindicated in smokers as it increased the risk of hypoglycemia due to greater absorption compared to nonsmokers. In addition, patients were required to undergo pulmonary function tests before treatment initiation, after 6 months and annually thereafter. This product did not do well commercially despite the noninvasive route possibly due to higher cost, the bulky delivery device, concerns related to declining in pulmonary function, and less preference by the patients and physicians. This product was withdrawn from the market by Pfizer in 2007.

Another promising inhaled insulin is Afrezza (Sanofi and MannKind) based on Technosphere^® dry powdered formulation. The onset of action of Afrezza inhaled insulin is 15 min and duration is 2-3 h, which is ideal for postprandial blood glucose control. Transient nonproductive cough and a modest reduction in lung function initially are the common side-effects. Recently, MannKind completed two large phase 3 clinical trials with the use of this device in patients with T1DM and T2DM (NCT01445951/NCT01451398) and a clinical trial is under investigation in patients with already compromised pulmonary function (NCT01021891). This device is in the FDA approval process.

The AERx insulin Diabetes Management System, Aerodose, ProMaxx (protein matrix microsphere) and advance inhalational research are newer inhalational devices being investigated in clinical trials. Recently, Sanofi has launched Afrezza in the United States market for diabetes management in patients with T1DM. Although, the pulmonary route of insulin administration is noninvasive, it is limited by technical issues associated with inhaler devices, higher cost and long-term safety especially pulmonary function. (3)

BUCCAL DELIVERY OF INSULIN:

Transmucosal delivery is a suitable route for insulin noninjection administration. Insulin delivered by buccal delivery system is through an aerosol spray into the oral cavity and hence, differs from inhalers. The insulin is absorbed through the inside of the cheeks and in the back of the mouth instead of the lungs. Nanoparticles are pelleted to impart three-dimensional structural conformity and coherence thereby facilitating of buccal delivery of insulin. In vivo studies performed on diabetic rats showed promising results with stable blood glucose profile with a significant hypoglycemic response after 7 h. similar studies in the rabbit and rat have shown that buccal spray of insulins an effective insulin delivery system, which is promising for clinical trial and future clinical application. Though results are promising in rat models, rats are not appropriate models as rats have a keratinized buccal mucosa. The only animal models comparable to the human buccal permeability are pigs. The continuous, but variable, saliva flow and the robust multilayered structure of the oral epithelium constitute another effective barrier to penetration of drugs. Oral-Lyn, Generex Biotechnology Corporation, Toronto, Canada is developing a buccal insulin formulation, based on Rapid Mist, advanced buccal drug delivery technology (www.Generex.com/technology.php). Oral lynis a liquid formulation of human regular insulin with a spray propellant for prandial insulin therapy. The insulin formulation is said to be stable at room temperature for more than six months. The formulation results in anaerosol with relatively large micelles (85% of that having a mean size > 10 μm) and therefore cannot go into the lungs. Each puff is claimed to deliver 10 U of insulin. Absorption rate of insulin administered as a puff is 10% and that corresponds to 1 U when one puff of 10 U is delivered. That translates to use of 10 puffs to deliver 10 U insulin for a meal; this undertaking can be considered time consuming and not user friendly. The insulin is claimed to be released from the device as a metered dose, identical from first puff to the last. Clinical studies in healthy volunteers and subject’s with type 1 DM and type 2 DM have shown that the oral insulin spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action when compared with regular insulin given subcutaneously. In all of the studies conducted, the oral insulin spray was generally well tolerated. Only side effects noted include mild, self-limited episodes of transient (1-2 min) mild dizziness during dosing in some healthy volunteers and subjects with type 1 DM. No changes in vital signs, laboratory values or physical examination results were said to have occurred. The product is said to be on the market in a number of countries (e.g., Ecuador and India). Without appropriately designed and performed phase II and trials at hand, it is not possible to make any clear statement about the benefits/risk ratio of the different buccal insulin. Some companies are quite active and asmall Israel-based company Oramed is in phase 2b.(3)

COLONIC INSULIN DELIVERY:

Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease, but also as a means of accomplishing systemic therapeutic goals. Large intestine is ideally not suited for absorption processes for drugs but it has certain advantages over small intestine like, long transit time, lower levels of peptidases (prevent destruction of peptides) and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Oral delivery systems intended for colonic release of insulin were devised according to micro flora-, pH-and time-dependent strategies were well described in a review by Maroni et al. Bioavailability and pharmacological availability data are generally still far from being reliable in terms of magnitude, onset, duration and above all, consistency for this route of administration and it is under investigation. Despite the enthusiasm and progress in making oral insulin, there is still a long way to go before these products will be available in the market. (4)

ORAL INSULIN:

The oral route of insulin administration may be the most patient-friendly way of taking insulin and it could more closely mimic physiological insulin delivery (more portal insulin concentration than peripheral). However, the challenges in making oral insulin include: Inactivation by proteolytic enzymes in the GI tract and low permeability through the intestinal membrane due to larger size and hydrophobicity of insulin resulting in poor bioavailability. Several pharmaceutical companies are engaged in developing carriers to protect insulin from GI degradation and facilitate intestinal transport of insulin to deliver insulin to the circulation with sufficient bioavailability.

Natural and synthetic nanoparticles have been used as a carrier or vehicle for insulin such as chitosan, liposomes, polymeric nanovesicles, polylactides, poly-ε, poly-alkyl cyanoacrylate and various polymeric hydrogels, although further discussion of these carriers or vehicles is beyond the scope of this review Certain oral insulin preparations such as Capsulin, ORMD-0801, IN-105, oral hepatic directed vesicles and Eligen completed phase 1 and phase 2 trials with promising results.

Recently, multifunctional polymers and self nanoemulsifying drug delivery system (SNEDDS) has been tried for oral insulin by Sakloetsakun et al. This SNEDDS was based on thiolated chitosan. The formulations in the presence or absence of insulin (5 mg/mL) were spherical with the size range between 80 and 160 nm. Entrapment efficiency of insulin increased significantly when the thiolated chitosan was employed (95.14% ± 2.96%), in comparison to the insulin SNEDDS (80.38% ± 1.22%). After 30 min, the in vitro release profile of insulin from the nanoemulsions was markedly increased compared with the control. In vivo results showed that insulin/thiolated chitosan SNEDDS displayed a significant increase in serum insulin (P = 0.02) compared to oral insulin solution. A new strategy to combine SNEDDS and thiolated chitosan described in this study could therefore be a promising and innovative approach to improve oral bioavailability of insulin.(4)

NASAL INSULIN:

In theory, intranasal delivery has several advantages over oral (bypass GI peptidases), subcutaneous (noninvasive and painless) and inhalation route (no issue with lung function) which makes this route attractive for the delivery of insulin. However, intranasal delivery has shortcomings such as limited permeability of a large molecule through the nasal mucosa and rapid mucociliary clearance resulting in variable absorption. Historically, intranasal delivery with early porcine and bovineinsulins was investigated in patients with T1DM. Currently, two technologies are under investigation: Nasulin™ (CPEX pharmaceuticals) and nasal insulin by Nastech Pharmaceutical Company Inc. Both insulin preparations have bioavailability of about 15-25% with the onset of action ~10-20 min. Results from the phase 2 and 3 clinical trials are awaited. The substances such as bile salt, surfactant and fatty acid derivatives are being investigated to enhance mucosal permeability of insulin but they increase the risks for local irritation, nasal secretion, sneezing or burning sensation. Nasal insulin crosses the blood brain barrier hence it has ahypothesized effect on memory function. In a randomized placebo controlled trial with 104 adults with amnestic mildcognitive impairment or mild to moderate Alzheimer’s disease were randomized to receive either placebo or 20 IU or 40 of intranasal insulin. Treatment with intranasal insulin improved memory, preserved caregiver-rated functional ability and preserved general cognition without any significant hypoglycemic event. These improvements in cognitive functions were correlated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Based on this, large randomized controlled trials (NCT01595646, NCT01767909) are ongoing to evaluate the use fulness of this agent for the treatment of Alzheimer’s disease.(3)

Transdermal insulin:

Transdermal insulin delivery is an attractive needle-free alternative and avoids the disadvantages associated with the invasive parenteral route of administration and other alternative routes such as the pulmonary and nasal routes. Permeation of compounds is limited to small, lipophilic molecules, as the stratum corneum, the outer most layer of the skin constitutes the major barrier. Several chemical and physical enhancement techniques, such as iontophoresis, ultrasound/sonophoresis, microneedles, electroporation, laser ablation and chemical enhancers, have been explored to overcome the stratum corneumbarrier to increase skin permeability. The advantages of transdermal drug delivery include convenience, good patient compliance, prolonged therapy, and avoidance of both the liver’s first-pass metabolism and degradationin the gastrointestinal tract. To improve transdermal delivery, microneedles have been regarded as a potential technology approach to be employed alone or with other enhancing methods such as electroporation and iontophoresis, as well as with different drug carriers (e.g., lipid vesicles, micro- and nanoparticles). As microneedles inserted into the skin of human subjects are reported to be painless, microneedles are a promising technology to deliver drugs into the skin.

Methods to improve transdermal delivery:

Chemical enhancers alter the lipid structure of the stratum corneum thereby reducing its barrier properties and increasing its permeability for drugs which would not pass through the skin passively. Iontophoresis is a technique that enhances the transdermal delivery of compounds through the skin via the application of a small electric current. Microneedle technology offers a cost-effective, minimally invasive, and controllable approach to transdermal drug delivery. It involves the creation of micronsized channels in the skin, thereby disrupting the stratum corneum barrier. Upon creation of the microchannels, interstitial fluid fills up the channels, resulting in hydrophilic pathways. Microneedles deliver the drug into the epidermis without disruption of nerve endings. Sonophoresis (phonophoresis) uses ultrasound and it has been shown to increase skin permeability to various low and high molecular weight drugs, including insulin. However, its therapeutic value is still being evaluated. Microdermabrasionis a method to increase skin permeability for transdermal drug delivery by damaging or removing skin’s outer layer, stratum corneum. Microdermabrasion can increase skin permeability to deliver insulin. Patches deliver basal insulin rather than a fast-acting bolus, hence are not useful for meal time boluses. Preliminary data on insulin-loaded micro-emulsions for transdermal delivery showed promise on goat skin. Altea Development Corporation is planning to introduce a product which will either be a one- or half-day patch, depending on the outcome of testing.(3)(Yaturu 2013)

OTHER NONCONVENTIONAL ROUTES (3):

Ocular route:

Until date, no human trial has been reported with this route and an animal study failed to achieve significant plasma insulin concentration.

Rectal route:

Rectal gels and suppositories showed fair results. However, this route is not commercially viable.

Intra-tracheal:

Administration of insulin was reported in 1924 but is not practical so not taken up for further development.

CONCLUSION:

Recent developments in insulin therapy have potential for reducing some of the negative aspects of current methods. Long-acting insulin, such as insulin degludec, may require less frequent injections. Fast-acting insulin, such as Viaject, have been shown to improve postprandial glycemic control and reduce hypoglycemia. The artificial pancreas (closed-loop systems with insulin pumps that deliver insulin in response to sensors) may prove to be a valuable therapy for type 1 diabetes patients, particularly if the lag period can be shortened through improved glucose sensors and the use of ultra-fast acting insulin. Of the alternative methods of administration, the oral routeis the most promising, especially with nanotechnology allowing for several types of encapsulations to bypass the gastric acidic environment. Oral delivery offers the benefits of ease of administration (leading to greater acceptance by patients), improved absorption rates, and mimicry of the normal route of insulin through the liver.

ACKNOWLEDGEMENT:

Authors are thankful to the trustees and management of MET’S Institute of Pharmacy, Bhujabal Knowledge city, Nashik.

REFERENCES:

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4. Rima B. Shah1, M. P., David M. Maahs, Viral N. Shah (2016). "Insulin delivery methods: Past, present and future " International Journal of Pharmaceutical Investigation 6(1).

5. Fry, A. (2012). "Insulin Delivery Device Technology 2012: where are we after 90 years?" Journal of Diabetes Science and Technology 6(4): 947-953.

6. Penfornis, A., et al. (2011). "Evolution of devices in diabetes management." Diabetes Technology & Therapeutics13(S1): S-93-S-102.

7. Shah, R. B., et al. (2016). "Insulin delivery methods: Past, present and future." International Journal of Pharmaceutical Investigation 6(1): 1.

8. Cohen, O., et al. (2009). "Improved glycemic control through continuous glucose sensor-augmented insulin pump therapy: prospective results from a community and academic practice patient registry." Journal of Diabetes Science and Technology 3(4): 804-811.

9. Burdick, P., et al. (2009). "Use of a subcutaneous inj ction port to improve glycemic control in children with type 1 diabetes." Pediatric Diabetes10(2): 116-119.

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Received on 24.06.2017 Accepted on 15.07.2017

Asian J. Res. Pharm. Sci. 2017; 7(4):189-196.

DOI: 10.5958/2231-5659.2017.00029.7

ABSTRACT: