INTRODUCTION:

DIEBETIES:

Diabetes Mellitus Type-II (DM-II) is a chronic metabolic disorder of carbohydrate characterized by high blood sugar because the cells do not properly use insulin. It has severely affected a large section of the population having a strong hereditary tendency (387 million people worldwide have diabetes at present). By the survey of World Health Organization (WHO) in 2010, more than 4 million people of age groups 20 to 79 have died due to (DM-II). WHO has also projected that diabetes death will double between by the end of 2030.

More than 80% of diabetes deaths occur in low and middle-income countries. Despite enormous efforts in developing newer leads and novel strategies for the management of diabetes, it remained the key concern across the globe. The search for alternative or unexplored classes of substances for managing hyperglycemia attracted the attention of scientists globally. India is one of the largest consumers of sugar in the world, owing to cultural and food habits. In the country, the diabetic population of the age group of 25-45 is about 15% and is quite increasing at an alarming pace. Along with the complications of DM-II, poverty remained the chief problem among the masses which impairs the regular management of hyperglycemia by pharmacological approach. Due to non-availability of the anti-diabetic drugs in rural areas, compromise in purchasing power, greediness towards sweet confectionaries and precipitation of secondary symptoms, cumulatively leads to decreased quality of life among DM-II patients. In most of cases, an artificial sweetening agent is incorporated.^]

However, in the majority of the cases, the safety of the chemical sweetener such as aspartame, cyclamate, saccharin, sucralose etc. is a big challenge.^[3]Natural products are the most promising therapeutic candidates in management or treatment of various ailments.

The anti-hyperglycemic effect of these formulation are for their ability to restore the function of pancreatic tissues by increasing insulin output or inhibit the intestinal absorption of glucose or to the facilitation of metabolites in insulin-dependent processes.] Stevioside, a glycoside obtained from Stevia rebaudiana Bert has the chief characteristic of regulating hyperglycemic episodes. Natural glycoside like stevia does induce hypoglycemic response when ingested, making them attractive natural zero calories or low calorie sweeteners to diabetic and miscellaneous carbohydrate-controlled diets. Many therapeutic agents or artificial sweeteners have the tendency to absorb in oral, buccal cavity and the acidic media. Medicated jellies are such examples that would permit more rapid therapeutic action by the patient of any age.

Therefore, the identification of natural products based jelly formulation to manage hyperglycemic episodes represents an attractive strategy to develop potential antidiabetic formulations. Even though several nutraceutical like Stevia Life and nanomedicine formulations have been developed by several companies over the years which do have both commercial value and applications as pharmaceutical aids. Based on the fact that stevia product containing jelly based formulation have not yet designed as hypoglycemic aids for over-the-counter (OTC) prospective. The main objective of this study was to develop a jelly based product containing stevioside which will impart glucose lowering as well as artificial sweetening characteristics, thereby will act as a drug system. The work is quite similar to the development of edible jelly brands like Juzt Jelly, Jelly Belly, Boleto, Jolly Candy, Frut Bite, etc. It was achieved by selection and characterization of drug candidate (stevioside) and their formulation components for systematic release of drug from jelly. It is convenient to administer anywhere, anytime and does not require water.^[3]

INSULIN:

Insulin was discovered in 1921 by banting and Best who demonstrated the hypoglycaemic action of an extract of pancrease prepared after degeneration of the exocrine part due to ligation of pancreatic duct. It was first obtained in pure crystalline from in 1926 and the chemical structure was fully worked out in 1956 by Sanger. Insulin is a two chain polypeptide having 51 amino acids and MW about 6000. The A-chain has 21 while B-chain has 30 amino acids. There are minor differences between human, pork and beef insulins: Thus pork insulin is more homologous to human insulin than is beef insulin. The A and B chains are held together by two disulfide bonds. Insulin is synthesized in the β cells of pancreatic islets as a single chain peptide Preproinsulin (110AA) from which 24 AAs are first removed to produce Proinsulin. The connecting or ‘C’ peptide (35AA) is split off by proteolysis in Golgi apparatus; both insulin and C peptide are stored in granules within the cell ^[9]

Assay:

Insulin is bioassayed by measuring blood sugar depression in rabbits (1U reduces blood glucose of a fasting rabbit to 45mg/dl)or by its potency to induce hypoglycaemic convulsions by its potency to induce hypoglycaemic convulsions in mice. 1 mg of the International Standard of insulin = 28 units. With the availability of pure preparations, it can now be assayed chemically also. Plasma insulin can be measured by radio immunoassay or enzyme immunoassay.^[9]

Regulation of Insulin secretion:

Under basal condition -1U insulin is secreted per hour by human pancreas. Much larger quantity is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.^[7]

Chemical:

The β cells have a glucose sensing mechanism dependent on entry of glucose into β cells (through the aegis of a glucose transporter GLUT2) and its phosphorylation by glucokinase. Glucose entry and activation of the glucoceptor indirectly inhibits the ATP-sensitive K channel resulting in partial depolarization of the β cells. This increases intracellular Ca availability (due to increased influx, decreased efflux and release from intracellular stores) →exocytotic release of insulin storing granules. Other nutrients that can evoke insulin release are-amino acids, fatty acids and ketone bodies, but glucose is the principal regulator and it stimulates synthesis of insulin as well. Glucose induces a brief pulse of insulin output within 2 min (first phase) followed by a delayed but more sustained second phase of insulin release.

INSULIN PATCH PUMP:

Insulin pump is a small computerized device that delivers insulin. Through out the day for the treatment of diabetes. It is appears to mimic the pancrease but you still have to monitor your glucose level and give it instruction for the correct amount of insulin to be released. It release insulin in two way

1) Basal Rate: where a small continuous quantity of insulin is released in between meals and overnight to keep a constant glucose level in the body.

2) Bolus Rate: where much higher insulin is released before meals to control the glucose release from the food you plan to eat.

Fig. 1: Insulin patch pump^[2]

Traditional insulin pumps and software have received broad acceptance because of their ease of use, accuracy, predictability, and ability to calculate bolus insulin doses basedon user-input information. Most of these traditional pumps deliver insulin through tubing that can kink, catch, andor detach. These tubing issues, along with the current size ofavailable pumps, often compromise discreet, convenient use. Taken together, these factors helped spawn interest in the development of patch pumps that involve no tubing, readilyadhere to the body, are small, lightweight, and completely or partially disposable, and are capable of being worn and manipulated discreetly under clothing^[11]

Problems associated withcurrently available patch pumps will have to be addressed, including temporary unavailability of a controller, pump size (form factor), adhesive intolerance, and poor adherence. A number of patch pumps are under development. Some patch pumps will require a separate controller device that communicates wirelessly with the pump, others will include all necessary control components. Specifications of pumps under development may change before the pumps reach market. Some pumps listed below as being currently unavailable or under development in the United States may already be available in other countries^.[1]

Historry of Insulin Patch Pump:

The first insulin pump designed by A Kadish was an intravenous pump with continuous glucose monitoring by an auto-analyser and an on and off mechanism when the blood sugars were not within normal ranges. It was a closed loop pump (Both glucose monitoring and infusion pump) much like artificial pancreas. Only that this device was as big as an army backpack and cumbersome to use.

The biostator was an instrument which used computer based algorithm for infusion rates and included an analyser of glucose values and insulin and dextrose pumps. It was as big as a desktop computer and was used for short term research purposes. Dr. Pfeiffer at the Ulm University, Germany played a significant role in miniaturization of Biostators. Some of his patients used to be seen carrying their biostators on prams during morning walks. Slama and group designed a device which only pumped insulin intravenously without glucose monitoring i.e. open loop, with a higher infusion rate prior to meals, a device very similar to the insulin infusion pump used during inpatient care. The use of the intravenous route was associated with complications related to thrombophlebitis, thrombosis and infections. Keen and Pickup from Guy’s hospital, London tried to circumvent these problems by designing a subcutaneous route of delivery. The first microprocessor controlled insulin pump was devised in the 1980’s. This first generation of pumps had many teething issues^.[4]

Fig. 2: General Diagram of Insulin patch pump ^[1]

MECHANISM ACTION OF INSULIN PATCH PUMP:

Insulin acts on specific receptors located on the cell membrane of practically every cell, but then density depend on the cell type. Liver and fat cells are very rich. The insulin receptor is a heterotetrameric glycoprotein consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds. it is oriented across the cell membrane as a heterodimer. The subunits carry insulin binding site. While the β subunits have tyrosine protein kinase activity.

Binding of insulin to α subunits induces aggregation and intermalization of the receptor along with the bound insulin molecules. This activates tyrosine kinase activity of the β subunits → pairs of β subunits phosphorylate tyrosine residues on each other → expose the catalytic site to phosphorylate tyrosine residues of insulin. Receptor substrate protein (IRS1, IRS2 etc) in turn, a cascade of phosphorylation and dephosphorylation reactions is set into motion resulting in stimulation or inhibition of enzymes involved in the rapid metabolic actions of insulin.

Certain second messengers like phosphoatidyl inositol trisphosphate (PIP3) which are generated through activation of a specific PI3 kinase also mediate the action of insulin on metabolic enzymes.

Fig 3: Mechanisum action of Insulin^[10]

Insulin stimulates glucose transport across cell membrane by ATP dependent translocation of glucose transporter GLUT4 and GLUT1 to the plasma membrane as well as by increasing its activity. Over a period of time it also promotes expression of the genes directing synthesis of GLUT4. Genes for a large number of enzymes and camers have been shown to be regulated by insulin primarily through map kinase. Activation of transcription factors also promotes proliferation and differentiation of specific cells.

The intermalized receptor insulin complex is either degraded intracellularly or returned back to the surface from where the insulin is released extracellularly^.[9]

Part of Insulin Pump:

The Continuous subcutaneous insulin infusion (CSII) pump, or insulin pump in short, consists of three parts, an infusion set,insulin reservoir and a computerised battery operated electromechanical pump.The infusion set is a thin plastic tube with a soft cannula at the end, similar to the intravenous cannula, although smaller, to be inserted under the skin to end in the subcutaneous tissue. The cannula end of the infusion set has an adhesive surface to hold it in place after insertion.A recent innovation has been the patch pump which has a reservoir unit that adheres to the patient’s skin and has an integrated infusion set, thus making it free of tubing.The insulin reservoir is similar to a regular syringe and has 2-3 days of insulin in it.The pump itself is the size of a pager and has within it the insulin reservoir, batteries, controls, display screen and a small battery operated motor that is linked to a computerised control module. The infusion set and the insulin reservoir are disposable and needs to be changed every 2 -3 days. Although the pump pushes insulin injections, it is still responding to changes made by the patient. Thus, the most important link in the use of the pump and thereby the outcome of its use, is the patient himself because all the directions for infusion control are controlled by the patient^.[4]

Marketed Patch Pump:

The Omni Pod Insulin Management System (Insulet Corp., Bedford, MA), the first patch pump marketed in the United States, delivers both basal and bolus insulin. It is composed of a pod, which must be replaced every 3 days, and a Personal Diabetes Manager (PDM). The pod contains, in addition to the pump, an insulin reservoir with a capacity of 2mL and a cannula. The PDM, which has an onboard glucometer, allows the patient to control the pod wirelessly and also features automated cannula insertion^.[13]

After receiving a blood glucose value from the fingerstick blood sample tested on the incorporated glucometer and anticipated carbohydrate (CHO) intake information from the patient, the PDM calculates mealtime bolus insulin dosage. The PD Mcontains a food library and also stores, displays, and downloads data on insulin delivery, blood glucose values, and CHO records. It is equipped with alarms=alerts and acolor LCD screen^.[1]

Fig 4: Omni pod Insulin patch pump ^[1]

Table 1: List of marketed patch pump

Company Product	Reservoir	Infusion Set	Basal Range	Bolus range	Details
INSULET CORP. Omnipod	200-Unit reservoir built into pod	Dose not use tubing. pod comes with a built in cannula that inserts with a button press on the PDM	From 0.05 to 30 unit per hour in 0.05 unit increments	From 0.05 to 30 unit increment of 0.05 or 1 unit. Insulin to-carb ratio in whole units only	No tubing .The system includes a waterproof pod that is warm is up to 72 hours and a remote personal Diabetes manager(PDM) that control the Pods function and has a built in blood glucose meter Once the pod is activated it is required to be within 5 feet of the PDM to deliver bolus doses.
MEDTRONIC DIABETES MiniMed 530G system	300-unit reservoir	Compatible with Medtronic infusion set only	From 0.025 to 35 unit per hour in 0.025. unit increment for up to 0.975 unit. Increment of 0.05unit for between 1 and 9.95 units. increment of 0.1 unit for 10 units or more.	From 0.025 to 25 units increment of 0.1 units. Alternate bolus increment available for greater precision Insulin carb ratio allows for fraction of grams.	The MiniMed 530G combo pump – CGM uses smart guard technology to stop insulin delivery for up to 2 hours if the glucose level reaches a preset low limit and user doesn’t react to a low-glucose alarm. (For more on its CGM function, flip to P.72) Remove pump body before bathing, swimming and doing other water activities. Works with glooko and Tidepool data management system, plus CareLink.personal software, which is compatible with windows and Mac operating system. Approved for use by adults and children 16 and over.
MEDTRONIC DIABETES MiniMed 630G system	300- unit reservoir	Compatible with Medtronic infusion sets only	From 0.025 to 35 units per hour in 0.025 units increments for up to 0.975 units. Increments of 0.05 unit for between 1 and 9.95 units. Increments of 0.1 units for 10 units or more.	From 0.025 to 25 units increments of 0.025 units insulin-to – carb ratio allows for fraction of grams.	The MiniMed 530G combo pump – CGM uses smart guard technology to stop insulin delivery for up to 2 hours if the glucose level reaches a preset low limit and user doesn’t react to a low-glucose alarm. (For more on its CGM function, flip to P 74) pump is waterproof for 12 feet deep for up to 20 hour.
TANDEM DIABETES CARE T-flex pump	480-units cartridge	Compatible with Tandem infusion sets only	From o.5 to 15 units per hours in 0.001-units increments	From 0.005 to 60 units in 0.01-units increments. Insulin-to-carb ration allows for fraction of grams	designed for people who require more than 1000 units of insulin per day. Color touch screen. Rechargeable battery with micro USB pump is watertight for up to 3feet deep for 30 minutes. Works with T: Conects Diabetes Management Application, Tandems web-based software Also works with Glooks, Tidepool, and Daisend data-management system. Approved for use by adults and children 212 and over.
TANDEM DIABETES CARE T-slim X2 pump	300-unit cartridge	Compatible with Tandem infusion sets only	From 0.1 to 15 units per hour in 0.001 –unit increments	From 0.05 to 25 units in 0.01 units increments with an option for up to an additional 25 units. Insulin to –carb ratio allows for fraction of grams .	The slim X2 uses the Tandam device Updater to remotely update software from a computer – without requiring purchase of a new device. integrated with the Dexcoms G5 CGM colour touch screen. Also work with Glooko,Tidepool ,and Diasend data –management system . Approved for use by adults and children 6 and over.

PATCH PUMPS APPROVED FOR MARKETING BY THE U.S. FOOD AND DRUG ADMINISTRATION BUT NOT YET COMMERCIALLY AVAILABLE IN THE UNITED STATES AT THIS WRITING:

The Solo_ MicroPump Insulin Delivery System (Medingo US, Inc., Tampa, FL) consists of a basal-bolus micropump, wireless remote controller, and cradle with a built-in cannula. The 2-mL insulin reservoir, which attaches to the pump, must be replaced at least every 2 days when insulin lispro or insulin glulisine is used and at least every 3 days when insulin aspart is used.

Patch pumps approved for U.S food:

The pump itself should be replaced every 90 days. Finesse_ (Calibra Medical Inc., Redwood City, CA) is adisposable mechanical pump that delivers insulin (bolus only). By depressing both its bolus-release buttons simultaneously, the patient will cause a bolus to be delivered. A separate driver will be used for inserting the cannula after the filled pump has been adhered to the body^.[12]

Fig 5: Solo -Micro pump^[1]

PATCH PUMP REPORTED TO BE UNDER

DEVELOPMENT

The Cellnovo Pump:

(Cellnovo Ltd. formerly StarbridgeSystems, London, UK) is a low-power, basal-bolus pump with an integrated power supply coupled with a reservoir containinga 3-day supply of insulin and a cannula for drug delivery. Two pump sizes are to beavailable: the reservoir in a pump for children is 0.5 mL, and that for adults is 1.5 ml. The empty reservoir and cannula are replaced after 3 days; the entire pump case is retained. This pump will utilize proprietary technology to control mechanical energy. It was projected to be available throughout Europe at the start of 2010.24 The Freehand_ system (MedSolve Technologies, Inc., Manhattan Beach, CA) for basal and bolus insulin delivery will consist of an electronically controlled pump usable for 3 months, a disposable insulin reservoir, a tubeless patch with contained cannula, and a remote control. The system will contain seven basal profiles. Basal delivery will be able to be temporarily suspended, and boluses can be delivered remotely or manually^.[1]

The Nanopump:

(Debiotech SA [Lausanne, Switzerland] and STMicroelectronics [Geneva, Switzerland]) for continuous subcutaneous insulin infusion will be equipped with a reusable aspect, containing the electronics, vibration alarm, buzzer, and capabilities for programming and remote control, and a disposable aspect, containing an insulin reservoir, pump, and batteries. The device’s adhesive patch containing an autoinserted infusion cannula is to be changed every 3 days. Several sizes of insulin reservoir will be available. The pump will be based on micro-electromechanical systems technology. ^[1]

The NiliPatch:

Disposable Insulin Pump system (NiliMEDIX Ltd., Tirat-Carmel, Israel) consists of a disposable insulin pump that delivers basal and bolus insulin. The pump uses a patented Pressure-triggered release mechanism and is controlled by a system of valves and sensors. The NiliPatch has been certified for marketing in the European Union and Israel^.[1]

The PassPort system:

(Altea Therapeutics Corp., Atlanta, GA) for delivery of basal insulin will comprise an applicator and Passport Patch, which contains a drug reservoir under which there is a small screen (porator) containing metallic filaments. The applicator delivers an electric charge to the porator, galvanizing the filaments and vaporizing the closest skin cells, creating micropores through which insulin passes transdermally.27 Drug delivery will be initiated by folding the patch after attaching it to the skin. The micropores created by controlled bursts of thermal energy permit the flow of not only insulin but also other proteins, peptides, and CHOs into the body without needles or pumps. Phase 1 clinical data indicate that the PassPort system provides sustained, therapeutic insulin levels^[1].

INSULIN PUMPS COUPLED WITH GLUCOSE SENSORS:

The combined use of real-time continuous glucose monitoring (RT-CGM) and continuous subcutaneous insulin infusion (CSII) via an external pump is a logical development with a view towards an artificial pancreas for the optimal treatment of type 1 diabetes. The goal is to implement an automated system or “closed loop” that permits the delivery of subcutaneous insulin adjusted to measured levels of subcutaneous glucose^.[5]

Non-automated coupling of insulin pumps and glucose sensors:

While awaiting the development of an artificial pancreas,a preliminary step is the non-automated coupling of an insulin pump to a glucose sensor. The combined use of both system appears consistent with the conceptual plan to optimalize use of the pump. The patient can continuously adjust the delivery of insulin based on the values and trends indicated by real-time data from the glucose sensor. This is an example of an “open-loop” device: the patient can maintain glucose control by interpreting the data from RT-CGM, and use it to modulate insulin basal rate, temporarily stop the pump and/or deliver additional insulin boluses. The theoretical value is such that systems incorporating insulin pumps and glucose sensors already available to patients. These sensor-augmented pump devices include a subcutaneous glucose sensor with a6 to 7 day lifetime that communicates via telemetry with an external insulin pump. The pump’s screen displays glucose sensor data and emits an audible alarm whenever high or low values are detected^.[5]

Effectiveness of RT-CGM associated with an insulin pump:

All of the studies with the exception of the first, confirmed the efficacy of RT-CGM associated with an insulin pump in reducing HbA1c, even though the benefit was sometimes observed only in subgroups of patients.

The first study involved poorly controlled type 1 diabetic patients already being treated with an insulin pump. These patients were randomized into two groups: the first continued with SMBG and pump therapy; while the second was treated with a sensor-augmented pump (the MiniMed Paradigm REAL-Time System). After 6 months, the HbA1c decrease of about 0.6% to 0.7% was similar in both groups. Although the overall results were negative in terms of added value with RT-CGM, post-hoc analysis highlighted the importance of how long the glucose sensor was worn. Of the patients using the sensor >60% of the time, there was an HbA1c decrease of almost 0.9% during the study. In contrast, the control of diabetes worsened in patients wearing the sensor < 60% of the time, with an HbA1c increase of almost 0.2%. ^[16]

Automated coupling of insulin pumps and glucose sensors for preventing hypoglycaemia:

Hypoglycaemia alerts are integrated into RT-CGM systems. However, the DirectNet Study Group showed that 71% of cases – specifically, children and adolescent patients – did not react to the hypoglycaemia alerts that occurred during sleep. This is important as most episodes of severe hypoglycaemia happen at night^.[5]

IMPLANTED PUMPS:

The use of implanted insulin pumps began enthusiastically a little over 20 years ago. The objective was to free the patient from the constraints of injections as well as to develop the components for an implantable artificial pancreas by taking advantage of the benefits derived from the use of intraperitoneal insulin delivery^.[14]

The intraperitoneal route:

Subcutaneous (SC) insulin absorption is slow, variable and induces secondary hyperinsulinaemia. These limitations have led to alternative routes being sought for continuousambulatory infusion of insulin. Studies in animals have shown the benefits of the intraperitoneal (IP) route, which has pharmacokinetics that are closer to physiological than the SC route. After delivery into the peritoneal cavity, insulin is primarily resorbed in the portal vein. There is an approximately 50% degradation during the first hepatic passage, thereby recreating a physiological insulin gradient between the portal vein and systemic circulation. Compared with the SC route, the IP route induces lower peripheral insulinaemia while allowing resorption and a faster return to baseline plasma levels. These insulin kinetics are more physiological, maintaining reproducibility of insulin profiles in the long term and resulting in an improved glucagon response to hypoglycaemia. The use of the IP route for type 1diabetes treatment^.[5]

DEVELOPMENT OF INSULIN PATCH-PUMP SYSTEMS:

The Micro pump Downloads The following are developmental patch pumps for which there is little available information: the Medipacs patch pump (Medipacs, Inc., San Diego, CA); the Medtronic, Inc. Patch Delivery system (Medtronic, Inc., Minneapolis, MN); and the Steady Med patch pump (Steady Med Ltd., Tel-Aviv, Israel), which is based on an electrochemical battery that expands, propelling a bolus, when a button is pressed^.[1]

12. Pump-Controlling Algorithms:

In general an algorithum uses a finite sequence of well defined instructions for completing a task, starting from an initial state and proceeding through computations to a desired end state. With a closed-loop system, an algorithm starts from a state of glucose level as supplied by a CGM and determines, through a series of equations, the desired end state, including the way in which insulin will be infused by a pump to maintain blood glucose within desired limits. Some of these equations may be able to take into account previously collected data reflecting the glucose–insulin responses of large numbers of patients. Most pump-controlling algorithms are computed within pump controllers.^.[14]

13. SENSOR-AUGMENTED PUMPS:

Pumps that display continuous glucose monitoring are already available (for example, the Medtronic Paradigm® Veo and the Animas® Vibe). Indeed, not only the actual glucose level, but also the alarms and trends displays can all help the patient to modify his insulin doses. These pumps may also be expected to adapt their calculators to the individual needs of the patient and to not only give advice in real time, but also on the basis of several days’ worth of glucose profiles. Such improvements are the next steps towards a closed-loop insulin delivery system^.[15]

14. INSULIN PUMP TREATMENT: DO WE NEED MORE?

Pump and catheter features Today’s insulin pumps are highly reliable and easy to use in daily life, at least as regards their basic functions. They have become smaller and more discreet but, also, in some ways, more complex, as many new technological features are now embedded in the pumps, including the different ways of infusing boluses, different patterns of basal rates for different days and reminders for boluses. Bolus calculators are particularly useful for helping patients to adjust their prandial doses. The capability to download data already exists, and may well be accompanied by automatic analysis of these data and by expert advice for treatment adjustment. However, whereas catheters have considerably improved over the past few years, the technical aspects of pump and catheter handling remain an obstacle for some patients. Filling the pump reservoir, priming the catheter and inserting the needle require precision, skill and time; however, patch pumps should bring about important improvements in this field. Also, avoidance of the catheter and automatic needle insertion/ retraction are attractive features that should reduce the discomfort of pump therapy for activities such as showering, sports participation and swimming^.[6]

ADVANTAGES:

1) Fewer needle pricks: The pump require a needle stick every 2-3 days in comparison to the multiple pricks in a single day from insulin injection.

2) precision: they allow accurate delivery of insulin to the 1/10^th that is beneficial to people sensitive to small doses, like children.

3) Dose calculation: pumps have a calculate that saves the user from the extra math by helping to determine the closes based on the carb intake blood glucose levels and the amount of insulin still active from the previous doses.

Flexibility convenience and spontaneity they allow early adjustments with buttons to either increase or decrease the bolus for accommondating the changes in daily life like dining out sports. Growth and illness or managing the down phenomenon.

Eliminate an predictable effect of lung acting insulin. They used rapid – acting insulin that has and efficient action for a short duration instead of intermediate or slow acting insulin that take a while to reach there peak values and tend to accumulate under the skin which makes it difficult predict the action of insulin.

Reduce episodes of sever low blood glucose by using rapid acting insulin and allowing better control of release insulin during or before of activities that tend to lower blood glucose you have less risk of having a hypoglycemic attack.

1) Pump improve A/c scores

2) Less glucose variability

3) Weight control

4) Lower risk of complication

5) Better quality of life

6) Data analysis pump store

7) Plethara of information that scan be used for analysis and treatment planning.

DISADVANTAGE

1) Cost:

Insulin pump are more expensive that the syringes. Although most insurance plans cover insulin pump and supplies there are often co-pays and deductibles to take case of there is also a difficulty in getting approval from NHS to cover the costs of the insulin pumps.

2) Steep learning curve:

It takes a few days for the user to get used to changing infusion sets. Getting the basal and bolas doses regulated and learning to avoid problems like bubbles.

3) Complication:

A higher risk of developing diabetic ketoacidosis if the pump malfunctions. This can happen if the battery is discharged. If the insulin is incultivated by heat expousure if reservoir runs out if the tubing becomes loose there is a leak of insulin or the catherter is bent on linked preventing delivery. Therefor it is important for pump user. To monitor their blood glucose levels frequently.

4) Inconvenience:

Since the pumps need to be wan all the time it can become an issue during sleep rough sports or doing activities like swimming the tubing can also get caught on hooks.

5) Skin Problems:

Users develop scar tissue in the area where the cannula is inserted these scar tissue do not head easily and soon develop lower insulin sensitivity that requires the user to change spots.

6) Changing issues:

Although the pump requires a change at every requires a change at every two –three days. The process is longer more involved.

7) Wastage:

Many units of insulin can be wasted while refilling the reservoir on changing the infusion site this can affect dosage information.

CONCLUSIONS:

Although inherent limitations in current technology make fully closed-loop system challenging, technologic advances make the ‘‘artificial pancreas’’ an increasingly realistic prospect. Discretion of patch pump platforms is appealing within closed-loop system, and many are under development. Insilin models are being refined and validated with various hardware combinations and will serve to accelerate regulatory review and approval of closed-loop systems on the horizon. Avoiding severe hypoglycemia would be a revolutionary change in diabetes management. Ultimately, an automated artificial pancreas may improve clinical outcome sand quality of life^.[1]

Despite the remarkable improvements in diabetes management thanks to the introduction of insulin analogues, a significant number of patients still cannot achieve their target HbA1c levels without experiencing disabling or severe hypoglycaemia. In such patients, pump therapy provides convenient and flexible insulin delivery while improving their glycaemic control and stability, and quality of life. In addition, efforts are being made to further improve insulin kinetics, and to develop user-friendly monitors and miniaturized insulin pumps. Appropriate teaching and training programmes are necessary, however, to achieve all of the benefits afforded by these technical improvements. Furthermore, considerable work is now in progress to develop algorithms for the automated regulation of glycaemia^[6]

Insulin pump systems have continually incorporated new components that have greatly benefited patients, including CGMs and wireless remote programmers. In the future, new devices including automobiles, watches, clocks, beds, and exercise equipment are all viable devices for inclusion (while phones may be adopted more, they are already a part of insulin pump systemtherapy). Analysis more difficult. We recommend a cautious approach to adopting these new devices, as their impact on patient safety is not well understood^.[2]

REFERENCE:

1. Henry anhatt, D.O, Nancy J.V. Bohannon M.D., Insulin patch pump: Their Devlopment and future in closed-Loop system, volume12 supplement 1, 2010; page no. S-51-S-56.

2. Nathanaenl paul, Ph. D, tadayoshi kohno, Ph.D., David C. klonoff, M.D., A Review of the security of insulin pump infusion system, volume 5, Issue 6, November 2011, Page No. 1557-1562

3. Mangesh Godbole; Debarshi kar Mahapatra; priya D. khode; Fabrication and Characterization of Edible Jelly Formulation of stevioside: A Nutraceutical or OTC Aid for the Diabetic Patient, Neutracceutical Volume 2017, Issue 2; ISSN 09763872; Page No.: 1 to 8.

4. Satinath, Mukhopadhyay; A Review Insulin pump; Institute of post Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Journal of the Indian Medical Association: November 2013

5. P. Schepelynck, P. Darmon, L. Molines, M.F. Jannot – Lamotte, C. Treglia, D. Raccah, Advances in pump technology: insulin patch pumps, combined pumps and glucose sensors, and implanted pumps, Diabetes and Metaboplism 37 (2011), page no. 585-593.

6. H. Hanaire. External insulin pump treatment in the day to day management of diabetes: benefits and future prospective, Diabetes and Metabolism 37 (2011) page no: 540-547.

7. Indian pharmacopoeia 1996, Government of India ministry of Health and Family Welfare, Published by the controller of publication Delhi. Volume – I,II.

8. British Pharmacopoeia 2007, Introduction general notice. Monograph Medicinal and Pharmaceutical Substance. Volume I,II,III,IV.

9. K.D. Tripathi M.D, Essentials of Medical Pharmacology, 5^th edition, 2003 published by Jaypee Brother Medical Publishers (P) Ltd. New Delhi. Page No. 235-239

10. F.S.K. BARAR MD., and Essentials of pharmacotherapeutics edition 1^st 1985, published by S. Chand New Delhi. Page no. 340-349

11. Guidance for Industry and FDA Staff—Total Product Life Cycle: Infusion Pump—Premarket Notification [510(k)] SubmissionsDraft Guidance. April 23, 2010. Available from: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm206153.htm. Accessed on October 31, 2011.

12. Senesh G, Bushi D, Neta A, Yodfat O. Compatibility of insulinLispro, Aspart, and Glulisine with the Solo MicroPump, a novelminiature insulin pump. J Diabetes Sci Technol. 2010:4(1):104–10.

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Received on 26.04.2019 Modified on 28.05.2019

Res. J. Pharma. Dosage Forms and Tech.2019; 11(3):206-216.

DOI: 10.5958/0975-4377.2019.00036.3