Advances In Diabetes Management: A Comprehensive Review of Novel Formulations for Optimized Insulin Delivery

Diabetes –

Diabetes is a frequent disease and its enormous complication is responsible. A complete lack of insulin leads to the release of carbohydrates, which is known as diabetes mellitus.  Diabetes is a dangerous disease that causes billions of dollars' worth of annual difficulties in the global healthcare system.  Diabetes is a collection of diseases characterized by elevated blood glucose levels and increased thirst, urination, and appetite. Diabetes affects people worldwide and has an economic impact on every country, but especially poorer nations.

At least 285 million people worldwide suffer with diabetes, according to the International Diabetes Federation. About 60% of people with diabetes worldwide live in Asia. By 2008, approximately 10% of Chinese adults suffered from an illness, up from less than 1% in 1980.^[16] In France UK in the US in the 1990’s. a recent French carried out a survey during first quarter of 1999. They showed prevalence of type 2 diabetes had growing the 5.7% annually between 1994-1999. ^[1] The components that go into diet quality also have their own effects. The risk of diabetes is linked to higher dietary glycemic load and Tran's fat. Physical exercise is also raised and hence the lowered risk of diabetes.

Diabetes is the sixth most common cause of death worldwide. Around 171 million individuals globally, or 2.8% of the population in 2000, have diabetes, according to the World Health Organization. Diabetes is treated with insulin. The pancreas secretes the hormone insulin, which helps cells use glucose and regulate blood sugar. ^[17]

Insulin that acts quickly begins to function within minutes and continues for hours. Short-acting or regular insulin takes around 30 minutes to completely activate and lasts for three to six hours. 2-4 hours of intermediate acting insulin will persist up to the final 18 hours. All day long, long-acting insulin is effective. Worldwide, almost 100 million individuals require insulin. Everyone with type 1 diabetes and 10% to 25% of the population with type 2 diabetes.
       
           
       
Fig 1.1:    Types Of Diabetes

Insulin-

In 1921, Banting and Best made the discovery of insulin. They show how an extract of pancreas made after the exocrine portion degenerates as a result of pancreatic duct ligation has hypoglycemia effects.^[23] It was originally discovered in pure crystalline form in 1926, and Sanger completely figured out its chemical composition in 1956.  ^[23] A protein or peptide hormone is insulin. It is produced by the pancreatic beta cells. Blood sugar levels, or glucose concentration, have an impact on beta cells.^[17] Insulin also prevents the liver from producing glucose. [17] Medical usage of insulin to treat specific types of diabetic mellitus. ^[23]

The molecular weight and amino acid composition of the human insulin protein is 51. Six Thousand. [23] The A-chain dimer contains 21 amino acids, while the B-chain contains 30.

Which are linked together by disulfide bonds. ^[23,17] The beta cell pancreatic islets generate insulin as the single chain peptide preproinsulin (110AA), from which proinsulin is initially made by removing 24 AAs.^[23]  Diabetes mellitus may develop if insulin level regulation is compromised. Protista and fungi are known to contain insulin-like proteins in addition to vertebrates.. ^[17]  Type II diabetes mellitus may caused by Beta cell are destroyed by an autoimmune reaction insulin can no longer be synthesized or be secreted into blood. ^[17] The INS gene encodes the precursor of insulin known as preproinsulin. Insulin levels in the blood can be measured. International units can be used to measure blood insulin levels. ^[17]

Different Novel Dosage Form Of Insulin Delivery System

Oral drug delivery system of Insulin-

Insulin delivery through the digestive tract offers a convenient method. because it enables the direct distribution of insulin in the liver through the portal of entry. Protease from the gastrointestinal system quickly inactivates insulin administered orally. As an attempt to prevent insulin from degrading, liposomes are used to deliver insulin, yet even this method fails when insulin is delivered straight to the stomach. It absorbs poorly. ^{[2, 3]}

Buccal drug delivery system of insulin-

medication delivery to the systemic circulation through the buccal mucosa. The majority of buccal formulations are made to release the active component gradually. The primary site of administration for the bioadhesive system is the mucous membrane. The mucous membranes of humans are comparatively porous, facilitating the rapid absorption of drugs. A sustained release of medication over an extended period of time is achieved by mucosal buccal administration. The frequency of dosing is being reduced. ^{[4, 3]}

Rectal drug delivery system of insulin-

Insulin has been given via suppositories, which pass through the rectal mucosa. in suppositories that combine different absorption enhancers with insulin. The level of absorption of insulin is superior to the oral route. There are side effects from insulin suppositories, include soreness or urgency in the rectal area. ^{[3, 5]}

Dermal drug delivery system of insulin-

Very little insulin enters the systemic circulation through the epidermis. After applying an electrical potential, it increases the transfer of insulin via the skin (iontophoresis). Low bioavailability is the result. the insulin molecules into lipid particle vesicles. Liposomes enhanced the delivery of insulin transdermally. ^[6]

Nasal drug delivery system of Insulin-

Insulin is administered through the mucosa of the nose or oropharynx. Insulin is formulated in a liquid form employing mixed micelle microfine membranes and absorption enhancers to improve absorption. It was intended to be used as a buccal spray with a straightforward inhaler dosage. After 10 minutes of delivery, the spray releases a tiny particle aerosol, and insulin starts to circulate throughout the body. It was discovered that using this insulin method decreased plasma levels of c-peptide and blood glucose. At roughly 10%, bioavailability is low. Nasal insulin has a very quick start of action and rapid absorption. After 10 to 15 minutes after administration, it happens. ^[7]

Pulmonary drug delivery system of Insulin-

The alveolar capillary barrier facilitates the passage of inhaled insulin. After inhaling, insulin starts to circulate throughout the body 10 minutes later, reaching its maximal effect after 60 minutes. Since the effects of inhaled insulin wear off faster, there may be a lower chance of hypoglycemia during the two to four hours following meals or at night. Bioavailability of inhaled insulin was reported to be 10-20%. Patients with type 1 and type 2 diabetes have participated in clinical studies using inhaled insulin. ^{[8, 9]}

Vaginal or intrauterine drug delivery system of insulin-

Insulin distribution via the vaginal mucosa during rectal administration can help stop presystemic breakdown. Insulin is being tried intravaginally in sheep as a lyophilized powder with bioadhesive starch microsphere and as an aqueous solution with lysophosphatidylcholin. In rats, insulin is also injected intrauterine and is absorbed in a physiologically active form in the uterus. ^{[14, 15]}

Various insulin delivery devices-

Needle and Syringe-

A hypodermic needle and hypodermic syringe are used to inject liquids or gasses into bodily tissues or extract them from the body. The capacity of syringes in this range is 1 ml, 0.5 ml, and 0.3 ml. The needle is specially coated and has an extremely fine point for injection. Insulin syringes are made to fit the standard U-100. the process of diluting insulin so that one milliliter contains 100 standard insulin units. ^[16]

Insulin Pen-

It is injected with insulin to treat diabetics. It is used in conjunction with disposable pen needles for dose distribution and dosage measurement. Compared to the conventional vial and syringe, it is more portable and convenient. It consistently has a more precise dosage. It hurts less to inject.^[17]

Insulin Pumps-

It is employed in the insulin administration process to treat type 1 diabetes mellitus. Its basal needs are met with fast-acting insulin thanks to the pattern of meals and activity. ^[17]

Insulin Jet Injectors-

As an alternative to T needles, the Insulin Jet Injector uses a pressurized jet of air to deliver a small spray of insulin into the skin. ^[20]

Insulin Patches-

Additionally, insulin patches are now being developed. However, insulin is not easily absorbed via the skin; instead, the patches release insulin gradually and constantly. Additional dose can be supplied by pulling out a tab on the patch. ^[20]

Insulin Inhaler-

are a novel approach to insulin delivery. Insulin inhalers function similarly to asthma inhalers, however they use the lungs to inhale dry powdered insulin into the circulation. Long-acting insulin can still be delivered because the technology can only be used to deliver fast acting insulin. ^[20]

Controlled Release System for insulin delivery

Controlled release system for subcutaneous delivery of insulin-

Subcutaneous injection is the classic approach of transport insulin into the body of someone with diabetes mellitus. The water soluble biodegradable triblock copolymer of poly-b-ethylene glycol-b-(D.L-Lactic acid co-Glycolic acid) (PLGA-PEG-PLGA) is an efficient injectable formulation for regulated release of insulin.Additionally, there was a steady rate of insulin release. in vivo after a single subcutaneous injection for two weeks. an insulin injection with controlled release utilizing microparticle technology.

 This long-acting injectable insulin composition lowers blood glucose levels and treats diabetes by combining insulin with crystalline dextran microparticles. For the treatment of insulin-dependent or -independent patients, two patients are using a controlled release insulin formulation. Acid stabilized insulin zinc ions and zinc binding ligand are two examples of this.The rest included protamine, zinc ions, insulin, and a ligand that binds reversibly to a R state insulin hexamer's His B10 site. ^[10]

Controlled release system for oral delivery of insulin-

The most physiological way to administer insulin is orally, as this allows the hormone to be delivered straight from the intestine to the liver. An 80-hour research conducted in vivo on diabetic mice revealed a 20–40% drop in baseline glucose levels. An further method of delivering insulin orally involves the use of a thiolate polymer called chitosan-4-thiobutylamidine (chitosanTBA), along with insulin.

The permeation mediator lowered the glutathione. After the non-diabetic rat was given the manufactured chitosanTBA insulin tablet orally, the insulin was released in a regulated manner over a period of eight hours. ^[11]

Controlled release for pulmonary delivery of insulin-

Inhaled insulin proves they are clinically useful. a dry powder for insulin inhalation having a bulk median aerodynamic diameter of 1-4um. It was jointly spray dried from hyaluronic acid (HA) and recombinant human insulin. Microparticle with a biodegradable ether-anhydride copolymer that can be used as a dry powder for inhalation and controlled medication release.

 ^{[12, 13]}

Advantages of controlled release drug delivery-

1. Reduced dosing frequency
2. Dose reduction
3. Improved patient compliance
4. Constant level of drug concentration in blood plasma.
5. Reduced toxicity due to overdose.
6. Reduces the fluctuation of peak valley concentration night time dosing can be avoided. ^[22]

Current route for insulin delivery and their problems-

Present mode of administration of insulin is subcutaneous route by in which insulin is presented in body in a no physiological. Subcutaneous administration of insulin has many challenges. Insulin injected subcutaneously at least twice a day. There disadvantages local pain, inconvenience of injection. When the over dosing result itching allergy, hyperinsulinemia.

And insulin clinical trials have shown on injectable insulin treatment. then patient fail to attain lasting glycemic control due to noncompliance because of these problems, novel approach for insulin delivery are being explored include oral transdermal, nasal, rectal, pulmonary, uterine, ocular, subcutaneous implant. ^[20]

Problems-

Enzymatic degradation of problems-

Insulin is degraded by the git. This is due to the fact that digestive systems are made to break down peptides and proteins equally. enzymatic breakdown by pancreatic proteolytic enzymes like alpha chymotrypsin and trypsin, as well as pepsin. Insulin is broken down by luminal breakdown in the gut and acid-catalyzed degradation in the stomach.^[20]

Intestinal transport of problems-                          

In the rat GIT, there was evidence of both active transport and biochemical evidence for insulin absorption. Researchers discovered that insulin is internalized by endocytosis after being absorbed to the apical plasma membrane. Through the endosomal route of tiny vesicles, it enters the basolateral plasma membrane and is secreted into the interstitial space. It is unknown if the surface of epithelial cells contains an insulin receptor. Erythrocytes have been shown to have insulin receptors on both their basolateral and apical surfaces. ^[20]

Stability problem-

The molecular structure in three dimensions is necessary for the activity protein. protein that can be broken down chemically and physically. Include structure up to a higher order structure in physical deterioration. in bond cleavage-based chemical degradation leading to the creation of new products. Proteins need to be described in terms of their size, shape, conformation, surface characteristics, and bioactivity. Spectrophotometric analysis, x-ray diffraction, differential scanning, colorimetry, and gel filtration were used to observe these alterations. A recent evaluation of research data examined the solid state stability of proteins in dose forms.^[20]

Challenges to Oral Insulin Delivery-

Insulin is one example of a protein or peptide that cannot be taken orally because of fast enzymatic breakdown. Due to its large molecular weight and lack of lipophilicity, the intestinal epithelium in the stomach is able to inactivate and digest the substance using a proteolytic enzyme.
Less than 1% of proteins and peptides are bioavailable when taken orally. Improving the bioavailability to between 30 and 50 percent is the problem here. ^[18]

Approaches for oral insulin –

Following oral delivery, peptides are not bioavailable from the GIT. Overcoming the enzymatic and physical obstacles and taking precautions to preserve bioactivity throughout formulation processing are necessary for these effective oral insulin administrations. in creating highly bioavailable oral protein delivery methods.^18]

• Modification of physicochemical properties such as lipophilicity and enzyme susceptibility.
• Addition of novel function to macromolecules.
• Use of improved carrier system.

Insulin administered via intramuscularly. It soon became clear that subcutaneous injection as a effective but considerably less traumatic.

Route of Administration

Drug delivery by membrane of the oral cavity can be classified as follows, by drug administration sites.

Subcutaneous Drug Delivery System –

Administering a drug subcutaneously involves injecting it into the adipose tissue directly beneath the skin. A bolus of subcutaneous injection is injected into the subcutis. the skin layer that lies just under the epidermis and dermis. referred known as the cutis together. Insulin can be administered very well by subcutaneous injection. When administered subcutaneously, it can result in swelling, redness, and burning sensations.^[3]

       
           
       
Fig. 1.2 Subcutaneous injection into the fatty layer of tissue under the skin

Intra muscular Drug Delivery System-

the injection, commonly into the thigh, gluteus, or dutoid muscles. When doctors cannot deliver an injection or no one with the necessary training is present, it might be challenging to administer an IV or even a SC injection. This method, however, is straightforward and easily accessible. When injected, intramuscular causes excruciating pain; tingling and numbers are also frequently experienced, and swelling and redness are unavoidably present.

       
           
       
Fig. 1.3 Intra muscular injection under the skin

Buccal Drug Delivery System -

A buccal drug delivery system is a method of delivering medication through the oral cavity's buccal mucosa. The buccal mucosa, which lines the inside of the cheeks, aids in blood flow. In terms of biology, the product is used to treat a localized systemic ailment by placing it between the cheek and upper gingiva (gums). Mucoadhesive medication delivery systems are ineffective because they produce GI discomfort and decreased bioavailability. They made use of this particular polymer's distribution technique. They stick to hydration, therefore they can be used to apply a medication to a specific area of the body for a long time.

Buccal absorption:

Buccal absorption leads systemic or local action via buccal mucosa.

Mechanism of buccal absorption:

Drugs are absorbed through the buccal intercellular gaps of the epithelium by passive diffusion of the non-ionized species, which is mainly controlled by a concentration gradient. The main mode of transport is the passive movement of non-ionic species over the buccal cavity's lipid membrane. It has been suggested that the buccal mucosa acts as a lipoidal barrier to medication absorption., This is the case with many other mucosal membranes, and the medicine is absorbed more easily the more lipophillic it is.A first order rate process could properly capture the kinetics of medication absorption through the buccal mucosa. There are a number of possible obstacles to buccal medication absorption that have been found. Salivary secretion modifies the drug concentration in the mouth, which in turn affects the buccal absorption kinetics from drug solution, as noted by Dearden and Tomlison (1971).^[35]

Factors affecting buccal absorption: Because there are numerous independent and interdependent variables that lower the absorbable concentration at the site of absorption, the oral cavity presents a complex environment for drug delivery.^[34]

1. Membrane Factors: This includes the lamina propria, intercellular lipids of the epithelium, surface area accessible for absorption, mucus layer of the salivary pellicle, and degree of keratinization.
   The thickness of the absorptive membrane, lymphatic and blood supply, cell renewal, and enzyme content will also help to lower the quantity and pace at which the drug enters the systemic circulation.
2. Environmental Factors:

a. Saliva: Salivary pellicle or film is the term for the thin layer of saliva that covers the whole buccal mucosa. Salivary film has a thickness of 0.07 to 0.10 mm. The thickness, content and mobility of this coating determine the rate of buccal absorption.^[34]

b. Salivary glands: The epithelium or deep epithelium of the buccal mucosa contains the small salivary glands. On the buccal mucosa's surface, they continuously release mucus. Mucus may act as a barrier to medication penetration even though it aids in the retention of mucoadhesive dose forms.^[34]

c. Movement of buccal tissues: The mouth cavity's buccal portion moves less actively. It is necessary to use mucoadhesive polymers to maintain the dosage form in the buccal region for extended periods of time in order to withstand tissue motions during speaking, eating, and, if feasible, swallowing.^[34]

Ideal Properties/Characteristics Of Buccal Drug Delivery System

• Should adhere to the site of attachment for a few hours
• Should release the drug in a controlled fashion
• Should provide drug release in an unidirectional way toward the mucosa
• Should facilitate the rate and extent of drug absorption
• Should not cause any irritation or inconvenience to the patient
• Should not interfere with the normal functions such as talking, drinking.

Limitations of buccal drug delivery system

• Drugs which are unstable at buccal pH cannot be administered.
• Drugs which have a bitter taste or unpleasant taste or an obnoxious odor or irritate the mucosa cannot be administered by this route.
• Drug required with small dose can only be administered.
• Those drugs which are absorbed by passive diffusion can only be administered by this route.
• Eating and drinking may become restricted.

Advantages of buccal drug delivery System

1. Drug is easily administered and extinction of therapy in emergency can be facilitated.
2. Drug release for prolonged period of time.
3. In unconscious and trauma patient’s drug can be administered.
4. Drugs bypass first pass metabolism so increases bioavailability.
5. Some drugs that are unstable in acidic environment of stomach can be administered by buccal delivery.
6. Drug absorption by the passive diffusion.
7.  Flexibility in physical state, shape, size and surface.
8. Rapid onset of action.
9. Improved patient compliance due to the elimination of associated pain with injections; administration of drugs in unconscious or incapacitated patients; convenience of administration as compared to injections or oral medications.
10. Increased ease of drug administration.

Disadvantages of buccal drug delivery System

1. Limited absorption area- the total surface area of the membranes of the oral cavity             available for drug absorption is 170cm2 of which ~50cm2 represents non-keratinized               tissues, including buccal membrane.
2. Low permeability of the buccal membrane: specifically when compared to the sublingual membrane.
3. The continuous secretion of saliva (0.5–2 l/day) leads to subsequent dilution of the drug.
4. Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and, ultimately, the involuntary removal of the dosage form.
5. Continuous secretion of the saliva (0.5-2 L/day)leads to subsequent dilution of the drug.
6. Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and ultimately the involuntary removal of the dosage form.
7. There are roughly 40–50 cell layers in the buccal mucosa epithelium, compared to slightly less in the sublingual epithelium. As they move from the basal layers to the surface layers, epithelial cells enlarge and flatten. It has been estimated that the buccal epithelium turnovers in 5–6 days, which is likely indicative of the oral mucosa turnover rate overall. The oral mucosal thickness varies according on the location: the gingival, floor of the mouth, ventral tongue, hard and soft palates, and gingiva vary between 100 and 200 ?m. The buccal mucosa measures between 500 and 800 ?m..^[35]

Method to increase drug delivery via buccal route –

• Absorption enhancers:

High molecular weight substances, such peptides, which typically have poor buccal absorption rates, have been shown to be effectively delivered via absorption enhancers. These could work through a variety of processes, include making the cell membrane more fluid, drawing lipids from within and outside the cell, changing surface mucin, or changing cellular proteins. The most widely used substances to improve absorption are fatty acids, azone, bile salts, and surfactants like sodium dodecyl sulfate. In a tissue culture model of the buccal epithelium, mannitol and fluorescently tagged dextran were similarly found to be better absorbed by solutions or gels of chitosan, whereas glyceryl mono oleates were found to improve peptide absorption through a co-transport mechanism.

• Permeation enhancers:

Permeation enhancers are substances that make the buccal mucosa easier to penetrate. The drug's physicochemical characteristics, the place of administration, the kind of vehicle, and additional excipients all influence the choice of enhancer and its effectiveness.
Mechanisms of action of permeation:

1. Changing mucus rheology:

By reducing the viscosity of the mucus and saliva overcomes this barrier.

2.  Increasing the fluidity of lipid bilayer membrane:

Disturb the intracellular lipid packing by interaction with either lipid packing by interaction with either lipid or protein components.

3.  Acting on the components at tight junctions:

By inhibiting the various peptidases and proteases present within buccal mucosa, thereby overcoming the enzymatic barrier. In addition, changes in membrane fluidity also alter the enzymatic activity indirectly.

4.  Increasing the thermodynamic activity of drugs:

Some enhancers increase the solubility of drug there by alters the partition coefficient. 

Table 1.1: Example of permeation enhancers with example

BIOADHESION:^[34]

‘Bioadhesive’ is defined as a substance that is capable of interacting with biological material and being retained on them or holding them together for extended period of time.

Bioadhesive are classified into three types.

1. Bioadhesion between biological layers without involvement of artificial materials. Cell diffusion and cell aggregation are good examples.

2. Bioadhesion can be represented by cell adhesion into culture dishes or adhesion to a variety of substances including metals, woods and other synthetic materials.

3. Adhesion of artificial substances to biological substrate such as adhesion of polymer to skin or other soft tissue.

Mechanism of Bioadhesion:

For bioadhesion to occur, three stages are involved:

 1. a close bond between a bioadhesive and a membrane that results from the bioadhesive swelling or from     a good wetting of the bioadhesive and membrane.

2. Penetration of the bio-adhesive into the tissue takes place.

3. Inter penetration of the chains of the bioadhesive with mucous takes place. Low chemical bonds can then settle.

4. Physical and chemical interactions, resulting from the expansion of the sticky material and chemical bonds caused by electrostatic interaction, hydrophobic interaction, hydrogen bonding, and dispersion forces, are the main ways that the mucus and biological substance bond.

Physiological factors affecting buccal bioavailability^[36]

1. Natural permeability of the epithelium: The permeability of the gut, which is highly specialized for an adsorptive function, and the skin, which is highly specialized for a barrier function, are intermediate in the case of the oral mucosal epithelium. The buccal mucosa of the oral cavity is less permeable than the sublingual mucosa.
2. Thickness of epithelium: The thickness of the oral epithelium varies greatly between regions in the oral cavity. The thickness of the buccal mucosa ranges from 500–800 ?m.
3.  Blood supply: The oral cavity is well-served by a robust blood supply and a lymphatic network in the lamina propria. As a result, medication molecules that cross the oral epithelium are easily absorbed into the systemic circulation.
4. Metabolic activity: Drug moieties that are absorbed through the oral epithelium enter the bloodstream immediately, bypassing the liver's and the gut wall's first-pass metabolism. For the delivery of enzymatically labile medications, such as therapeutic peptides and proteins, oral mucosal delivery may therefore be especially appealing.
5. Saliva and mucus: Because of the salivary gland's activity, a stream of 0.5 to 2 liters of saliva is produced daily to continuously wash the oral mucosal surfaces. Particularly the sublingual region is frequently exposed to saliva, which can improve drug breakdown and hence raise bioavailability.
6. Capacity to hold delivery system: Because the buccal mucosa has a smooth, mostly immobile surface, it is a perfect fit for retentive delivery systems.
7. Variations between species: Because of their highly keratinized epithelium, rats are not the best choice for animal models to research the administration of drugs through the buccal mucosa.^[36]
8. Routes and mechanisms of transportation: There are two primary pathways by which drugs can penetrate the epithelial barrier: amongst neighboring epithelial cells;
   The pathway through the cell membrane: through any of the following mechanisms: passive diffusion, carrier-mediated transport, and endocytic processes—across the epithelial cells.

Insulin-

Chemical Name- 21A- Glycine-30Ba-1-arginine-30Bb-1-arginine insulin

Categories- antidiabetic

Molecular weight- 6062.955g/mole or 6063 Daltons

Molecular Formula- C₂₆₇H₄₀₄N₇₂O₇₈S₆

Solubility – It is soluble in water, dilute acetic acid and dilute hydrochloric acid.

Dose - 0.5-0.8 unit/kg/day.

Pharmacokinetic -

Absorption – insulin administered via SC injection is absorbed directly into the bloodstream, with the lymphatic system playing minor role in transports.

Melting Point- 81⁰ C.

Hydrophobicity- 0.098

Isoelectric point – 6.88.

t_max – 8 hrs.

C_max – 13.6 mg/ml.

 AUC – 329 uU/1/180min.

Distribution – circulating insulin is distributed in equilibrium between free insulin and insulin bound to IgG antibodies.

Volume of Distribution- 3.2 L/Kg.

Protein Binding- 80-90%            

       
           
       
Fig.1.4 Structure of Insulin