1. INTRODUCTION:

Diabetes is a problem for people all around the world. The International Diabetes Federation says that 589 million adults have diabetes. This number is going to get even bigger to 853 million by the year 2050. Diabetes is very serious. It caused over 3.4 million deaths in 2024. It also costs a lot of money over one trillion dollars to take care of people with diabetes. Most people with diabetes live in countries where they do not have access to doctors and hospitals. There are two kinds of diabetes Type 1 and Type 2. Both kinds need medicine, like insulin to help control the diabetes. Insulin is very important for people with Type 1 diabetes and for some people with Type 2 diabetes.¹ The way we give insulin with shots under the skin is not very good. Many people are scared of shots. They do not like getting them. Some people even stop taking their insulin because they do not like the shots. This can make their diabetes worse. The shots can also cause problems, like pain and bumps under the skin. So doctors and scientists are looking for ways to give insulin and other diabetes medicines. One way they are trying is to use patches on the skin. These patches have needles that help the medicine get into the body. This way is less painful. It can be easier for people to use.² The skin is like a wall that keeps things out of our body. It also keeps good things, like medicine from getting in. The special patches help the medicine get through the skin wall. The patches are very small. They do not hurt much. They can also help the medicine get into the body slowly over time. This is a good way to give medicine to people with diabetes. It can help them take their medicine every day. It can make their lives better. The scientists are still working on this. They are trying to make it even better. They want to make sure it is safe and that it works well for everyone.^3,4 The main problem with getting medicine through the skin is that the skin is very good at keeping things out. The skin has a layer on top that is like a brick wall. This layer keeps molecules like insulin from getting through. The molecules are too big. They cannot fit through the small spaces in the skin. So the scientists are trying to find ways to get the molecules through the skin without hurting it. They are using patches and other methods to help the medicine get into the body. This is a hard problem to solve but they are working hard to find a solution. They want to help people with diabetes have a time taking their medicine and living their lives.^5,6 Diabetes is a problem but the scientists are working hard to find new and better ways to help people with it. They are trying to make the medicine easier to take. They are working on new ways to give it to people. This is good news for people with diabetes and it can help them have better lives.

2. Basics of Getting Medicine through the Skin:

The skin is the organ in our body and it helps keep us safe from bad things. It also makes it hard for medicine to get in. To get medicine through the skin we need to understand how the skin works and what makes it hard for the medicine to get through.

2.1 The Skin Barrier: The Top Layer and the Problems for Big Molecules:

The top layer of the skin is like a brick wall. It is very hard for molecules, like insulin to get through. The molecules are too big. They cannot fit through the small spaces in the skin. The skin also has helpers that break down the molecules, which makes it even harder for them to get through. The molecules that we use to help people with diabetes are very big. They are much bigger than the spaces, in the skin. So it is very hard for them to get through. The scientists are trying to find ways to help the molecules get through the skin without hurting it. They are using patches and other methods to help the medicine get into the body.^6,7

2.2 Passive vs. Active Transdermal Delivery:

Transdermal delivery strategies are broadly classified into passive and active approaches.

Passive delivery relies on the physicochemical driving force (concentration gradient) and formulation optimization to enhance permeation. Traditional transdermal patches (e.g., nicotine or fentanyl patches) use this mechanism successfully for small, lipophilic molecules (log P 1–3, MW<500 Da). For peptides, passive approaches incorporate chemical penetration enhancers (e.g., azone, fatty acids, terpenes), nanocarriers (liposomes, ethosomes, solid lipid nanoparticles), or prodrug strategies. However, passive methods alone have shown limited success for large peptides like insulin, typically achieving very low and variable bioavailability.^8,9

When it comes to getting things into our skin, there are a few ways to do it. Some methods actually break down or go around the skin's outer layer, called the stratum corneum, to make tiny channels or help things get in more easily. These methods include using tiny needles, special currents, sound waves, electricity, lasers, or high-pressure jets. One of these methods, using tiny needles, has gotten a lot of attention for helping people with diabetes. This is because it's a way to get medicine into the skin without hurting, and it's easy to use. The medicine goes into the layer of skin where there are a lot of tiny blood vessels, which helps it get into the body quickly. These active methods can get a lot more of the medicine into the body than other ways, often 20-80% more, depending on how they're designed.¹⁰

2.3 Peptide Physicochemical Properties Affecting Skin Permeation:

Several key physicochemical properties of peptides critically influence their transdermal delivery potential:

· Molecular weight: Permeation decreases exponentially with increasing size. Peptides >1 kDa generally require active enhancement.

· Lipophilicity (log P): Highly hydrophilic peptides (log P<0) exhibit poor partitioning into the lipid-rich stratum corneum.

· Charge and ionization: Net charge at skin pH (≈5.5) affects interaction with skin lipids and transport pathways.

· Conformation and stability: Peptides are prone to aggregation, denaturation, and proteolytic degradation during formulation and skin transit.

· Solubility: High aqueous solubility is advantageous for loading but detrimental for passive partitioning.

Understanding these properties has driven rational design strategies, such as temporary charge neutralization, cyclization, or conjugation with permeation-enhancing moieties. Formulation scientists also optimize pH, use co-solvents, and incorporate stabilizing excipients to maintain peptide integrity.^11,12

3. Microneedle Arrays (MNs) for Diabetes Peptide Delivery:

Microneedle arrays have emerged as the most promising technology for minimally invasive transdermal delivery of peptide therapeutics in diabetes. By creating transient microchannels through the stratum corneum, microneedles enable direct delivery of large hydrophilic molecules such as insulin and GLP-1 receptor agonists into the viable epidermis and dermis, bypassing the primary skin barrier while avoiding the pain and complications associated with subcutaneous injections.

3.1 Types of microneedles:

There are different kinds of microneedles that have been created, and each one has its own benefits when it comes to delivering peptides. Dissolving microneedles are among the most extensively studied for diabetes applications. Fabricated from water-soluble polymers (e.g., polyvinylpyrrolidone, hyaluronic acid, carboxymethylcellulose, or sugars), they dissolve rapidly upon insertion, releasing the encapsulated peptide payload. These offer high drug loading capacity, eliminate sharp waste, and provide excellent patient safety. However, they can suffer from limited mechanical strength and potential peptide instability during the drying process. Coated microneedles are made up of a strong center, usually made of metal or a special kind of plastic, and covered with a thin layer of a peptide mixture. When inserted, they release the drug quickly, but they can only hold a small amount of the drug, typically in tiny amounts. This makes them better suited for strong peptides, like GLP-1 analogs, rather than insulin, which needs to be given in higher doses.^13,14 These tiny needles work like small versions of the needles you'd find in a doctor's office, but instead of giving shots, they help get special liquids into the body. They can hold more liquid than other methods and can be used to give a big dose all at once or a steady stream over time. However, there are some problems that can come up, like the needles getting clogged or leaking, and making them is a bit more complicated. Hydrogel-forming microneedles are made from cross-linked hydrophilic polymers that swell upon insertion, creating conduits for drug diffusion from a separate reservoir patch.¹⁵microbio They offer high mechanical strength, reusable otential, and controlled release profiles, making them attractive for sustained peptide delivery. Solid microneedles are primarily used for skin pre-treatment (poke and patch approach), where the skin is punctured first, followed by application of a conventional patch.^16,17

3.2 Fabrication Techniques:

Microneedle fabrication has advanced significantly, enabling scalable and reproducible production. The most common method is micro-molding, which involves pouring polymer-peptide solutions into polydimethylsiloxane (PDMS) molds followed by centrifugation and drying. This technique is cost-effective and suitable for dissolving and hydrogel-forming microneedles. 3D printing is really taking off when it comes to quickly making prototypes and customizing tiny needle designs. This technology, especially digital light processing and two-photon polymerization, gives us a lot of control over the shape and structure of these tiny needles, and we can even use different materials to make them. There are other ways to make these tiny needles, like using special tools to carve out patterns on silicon or cutting metal into tiny arrays. Some methods use lasers to cut out the shapes or tiny machines to mill them out. Others use electricity to draw out thin threads or spray dry coatings onto the needles. Recently, people have started using 3D printing along with molding to make lots of these needles quickly while keeping their tips sharp and their arrays uniform. This combination of techniques is helping to make high-throughput manufacturing possible.^18–20

3.3 Design Parameters:

Optimal microneedle design is critical for effective skin penetration, mechanical strength, and drug delivery efficiency. The height of microneedles can vary, usually between 150 and 900 micrometers. For a pain-free experience, shorter microneedles, around 200 to 400 micrometers, are best for delivering things into the epidermis, the outer layer of skin. On the other hand, longer microneedles, ranging from 600 to 900 micrometers, can reach the dermis, the layer of skin beneath the epidermis, which allows for faster absorption into the system. Density usually varies between 100 and 600 needles per cm². Higher density increases drug delivery capacity but may reduce penetration efficiency due to the “bed of nails” effect.^21,22 Geometry significantly influences performance: pyramidal and conical shapes with sharp tips (<10µm radius) demonstrate superior skin insertion. Base diameter, aspect ratio, and tip angle are carefully optimized. The choice of materials has a big impact on how well something works with the body, how strong it is, and how well it keeps drugs stable. Some materials, like hyaluronic acid, polyvinyl alcohol, and a combination of lactic and glycolic acid, are really good at being compatible with the body. These are often used to make tiny needles that can deliver drugs or vaccines. For the needles that are coated or solid, people have used metals like stainless steel, titanium, and silicon, but lately, they're leaning more towards using plastic-like materials because they're less likely to break and don't pose as much of a risk to health and the environment. This is especially important when it comes to using these needles in real medical situations.²³

3.4 Loading and release kinetics of GLP-1 analogs:

Achieving sufficient peptide loading while maintaining stability and controlled release remains a major challenge. In dissolving microneedles, peptides can be loaded throughout the needle matrix or concentrated in the tip to maximize delivery efficiency. Loading capacities for insulin typically range from 5–50IU per array, depending on design. GLP-1 analogs, being more potent, require lower doses and are easier to incorporate.²⁴

Release kinetics vary by type:

· Dissolving microneedles often show rapid burst release (within 5–30 minutes) followed by sustained delivery.

· Hydrogel-forming systems enable more controlled, diffusion-based release over hours to days.

· Coated microneedles provide very fast release (seconds to minutes).

· Several strategies have been explored to achieve desirable pharmacokinetics, including multilayered microneedles, pH-sensitive coatings, glucose-responsive materials (e.g., phenylboronic acid-modified polymers), and incorporation of nanoparticles or cyclodextrins for stabilization.

Researchers have found that special tiny needles, called microneedles, can deliver insulin almost as well as a traditional shot under the skin. In fact, they can get up to 70-90% of the insulin into the body, which is really close to the traditional method. Plus, the way the insulin works in the body can be just as good, or even better, with these microneedles - it can start working faster and be more consistent. But to make this work, the scientists have to be very careful about how they mix the insulin with other ingredients and how they store it, so the insulin doesn't get damaged.^25,26

4. Transdermal Patches and Advanced Reservoir Systems:

Transdermal patches have been around for a while as a way to get medicine into the body without using needles. But when it comes to using them for diabetes treatments that involve peptides, the regular patches haven't worked so well. So, scientists have been working on creating new and better systems, like advanced matrix, reservoir, and hybrid patches, that can get past the skin's natural barrier more easily.

4.1 Matrix-type and reservoir-type patches:

The most common type of patch is the matrix kind, where the medicine is spread evenly throughout a sticky layer. When you put it on, the medicine goes straight from the patch into your skin. These patches are easy to make, thin, and flexible, and they stick well to your skin. But for big molecules like insulin that love water, these patches don't work very well because the medicine has a hard time getting through the top layer of skin. Also, you can't put too much medicine in the patch because it can't dissolve well in the sticky part and might not stay stable. Reservoir-type patches contain a separate drug reservoir compartment, usually a gel or solution, separated from the skin by a rate-controlling membrane. This design allows higher drug loading and more precise control over release kinetics. Reservoir systems can maintain a constant concentration gradient, potentially enabling zero-order release. Despite these advantages, traditional reservoir patches have shown limited success for peptides without additional enhancement strategies. Issues such as leakage, patch bulkiness, and potential skin irritation from membrane components have restricted their clinical application in diabetes.^3,27

4.2 Enhancer-integrated and stimuli-responsive patches

To improve peptide permeation, modern transdermal patches increasingly incorporate chemical penetration enhancers and physical enhancement technologies. These enhancers temporarily disrupt the lipid organization of the stratum corneum or create aqueous pores, facilitating peptide transport. Researchers have made a big step forward with patches that can react to their surroundings. These special patches can feel when things around them change, like the amount of sugar in the blood, how acidic or basic it is, how hot or cold it is, or even when they're exposed to light. One type of patch that's really interesting is the kind that responds to sugar levels in the blood, which could be a game-changer for people with diabetes. These patches have special parts that can detect sugar, like a molecule called phenylboronic acid or an enzyme called glucose oxidase, and when they sense that sugar levels are too high, they release insulin or a hormone called GLP-1 to help bring those levels back down. The goal is for these patches to work more like the body's natural insulin-release system, which is a big improvement over just getting shots.²⁸ Some other advanced patch designs can release peptides when needed or over a long period of time. These patches are sensitive to things like pH levels, temperature, or light. By using nanotechnology, like putting peptides in tiny particles called liposomes, nanoparticles, or exosomes, the patches can keep the peptides stable, protect them from breaking down, and help them get through the skin better. This can make the patches more effective and useful for delivering peptides to the body.²⁹

4.3 Combination with microneedles (MN-assisted patches):

The most promising strategy for effective peptide delivery combines microneedle arrays with transdermal patches, often termed MN-assisted patches or “poke and patch” and “patch-integrated microneedle” systems. The poke and patch method is a way to get medicines into the body. First, tiny needles that are solid or dissolve are used to make small holes in the skin. Then, a special patch with a peptide, which is like a tiny piece of protein, is put on the skin where the holes were made. This helps the peptide get into the body better, so it can work properly to make people feel better. It's especially good for bigger peptides that have a hard time getting into the body on their own. Some of the more advanced patch systems have tiny needles made of a special material that dissolves or swells up when it gets wet. When you put the patch on your skin, these tiny needles poke through the skin and then dissolve or swell, releasing the medicine. This can happen either from the needles themselves or from a tiny reservoir that's connected to them. The good thing about these systems is that they combine the best of both worlds - the tiny needles are really good at getting through the skin's defenses, and the patch is great at holding a lot of medicine and releasing it slowly over time, making it easy to use.^30,31 New research has shown that patches helped by microneedles, or MN, can get insulin and other medicines into the body really well - about 50-85% of the time. This is even better than shots under the skin, which can be a bit unpredictable. One type of patch that's really promising is the hydrogel kind. It forms tiny channels that help the medicine spread out slowly over time, so you might only need to put on a new patch once a day, or even less often. This could make it a lot easier for people to take their medicines and stay healthy. Furthermore, wearable patch designs with flexible electronics are being developed to integrate real-time glucose monitoring with on-demand peptide delivery, moving closer to a closed-loop transdermal artificial pancreas system.³²

5. Skin Penetration Strategies and Enhancement Techniques:

Effective transdermal delivery of peptides for diabetes management requires overcoming the formidable barrier properties of the stratum corneum. A wide range of chemical, physical, nanotechnological, biomechanical, and formulation-based strategies have been developed to enhance skin permeation while maintaining peptide stability and patient safety.

5.1 Chemical Enhancers and Physical Methods:

Chemical penetration enhancers are among the most widely investigated approaches. These compounds temporarily disrupt the intercellular lipid matrix of the stratum corneum or increase drug partitioning. Common classes include fatty acids (e.g., oleic acid), terpenes (e.g., menthol, limonene), surfactants, bile salts, and azone derivatives. While effective for small molecules, their utility for large hydrophilic peptides such as insulin and GLP-1 analogs is limited. Higher concentrations often required for peptides can cause skin irritation, erythema, and compromised barrier function. There are ways to improve how things get through our skin. Some methods can help bigger molecules pass through more easily.³³ Using a small electric current, iontophoresis helps get special molecules into the skin. It's like a tiny push that gets these molecules moving. This can be really helpful for getting medicines like insulin into the body. It's also good for getting a medicine called GLP-1 in, which can help with diabetes. The best part is that it can be controlled, so the medicine is released when it's needed. But, there are some downsides. If it's used for too long, it can irritate the skin. And, the way it's designed, with the electrodes and the strength of the current, can be limiting. Sonophoresis (low-frequency ultrasound) creates cavitation bubbles that disrupt lipid bilayers, forming transient aqueous channels. Combined with microneedles, it significantly enhances peptide transport. Electroporation applies short, high-voltage pulses to create temporary pores in cell membranes and the stratum corneum. Although highly effective for increasing permeability, its clinical translation has been slow due to the need for specialized devices and potential patient discomfort. These physical methods are often used synergistically with microneedle arrays to achieve higher and more reproducible bioavailability.³⁴

5.2 Nanotechnology Integration:

Nanotechnology has emerged as a powerful strategy to protect peptides and enhance their skin permeation. Liposomes, ethosomes, and transfersomes are lipid-based vesicles that can encapsulate peptides, improving stability and facilitating transport through the skin’s lipid pathways. Deformable vesicles (transfersomes) can squeeze through intercellular spaces, showing improved delivery of insulin in preclinical studies. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) offer better stability and controlled release. They protect peptides from proteolytic degradation in the skin and can be surface-modified with penetration-enhancing ligands.³⁵ Exosomes and cell-derived vesicles have gained attention due to their natural biocompatibility and ability to carry large macromolecules.³⁶ Recent studies demonstrate that exosome-loaded microneedle patches can achieve efficient transdermal delivery of GLP-1 analogs with reduced immunogenicity. Nanoparticles can be added to special tiny needles that dissolve in the skin, or to patches that hold a reservoir of the treatment. This gives two benefits: the tiny needles help the treatment get into the skin, and the nanoparticles help it spread through the skin's tiny channels.^37,38

5.3 Biomechanical and Formulation-based Strategies:

Biomechanical strategies focus on optimizing microneedle design and application techniques. These include increasing needle density in specific patterns, using tapered or bullet-shaped geometries for better insertion, and applying gentle pressure or vibration during insertion to improve penetration uniformity.³⁹

Formulation-based approaches are equally critical. These include:

· pH adjustment and ion-pair formation to optimize peptide charge and lipophilicity

· Use of co-solvents and supersaturated systems

· Cyclodextrin complexation for improved solubility and stability

· Prodrug strategies that temporarily mask hydrophilic groups

· Incorporation of protease inhibitors to reduce enzymatic degradation in the skin

Advanced formulation strategies also involve stimuli-responsive materials (glucose-, pH-, or temperature-sensitive) that enable controlled or on-demand release of insulin and GLP-1 analogs, moving closer to closed-loop delivery systems.⁴⁰

5.4 Safety and skin Recovery Assessment:

Safety evaluation is essential for clinical translation of these enhancement strategies. Most studies report that microneedle-induced microchannels close within 4–24 hours, with complete recovery of skin barrier function (measured by transepidermal water loss — TEWL) usually occurring within 48hours. However, the addition of chemical enhancers or physical methods can prolong recovery time and increase the risk of local irritation.⁴¹ When we use something on our skin for a long time, there are some concerns that come up. One of these is that our immune system might get a little too sensitive. We also worry about how it affects the tiny living things on our skin, like bacteria, and what happens when we use it a lot. But so far, studies have shown that it's usually okay to use, with just a little redness now and then. This redness is mild and doesn't last long. It seems that our skin is good at dealing with it, and it doesn't trigger a strong reaction from our immune system. This might be because our skin has a lot of special cells that help it get used to things, rather than fighting them off.⁴²

6. Patient-Centric Advantages Over Subcutaneous Injections:

Giving shots under the skin is a common way to take some medicines, like insulin and hormones. But it can be a hassle for people with long-term health problems. There are other ways to take these medicines that might be easier and less painful. For example, some medicines can be taken by mouth, which can make a big difference for people who are scared of needles or have problems with injection sites. This can also help people stick to their treatment plans and get better results in the long run. By making it easier to take medicine, we can help people manage their health better and feel more in control. This is especially important for people who have to take shots all the time, as it can get tiresome and affect their daily lives.⁴³

6.1 Pain Reduction and Improved Adherence:

One of the biggest benefits of oral alternatives is that they can greatly reduce or even get rid of the pain and discomfort that comes with injections. A lot of people feel anxious or scared of needles, which can make them put off starting treatment or even refuse it altogether. But with oral alternatives, this problem goes away completely. Instead, people can take their medication in a way that's easy and familiar, like swallowing a pill. This makes it a much more appealing option for many patients.⁴⁴ Reducing pain makes a big difference in how well people stick to their treatment plans. Research on GLP-1 therapies, such as semaglutide, has shown that both oral and injectable forms are effective, but many patients prefer oral options because they are more convenient and less stressful. The hassle of injections can lead to people stopping their treatment, but oral formulations can help people start and continue their treatment, especially for conditions like type 2 diabetes where there is often a reluctance to start using injectables. Looking at real-world data, it's clear that avoiding needles can help people overcome their concerns about their disease getting worse or their treatment not working, which can happen when they start using injections. By making treatment easier and less painful, oral formulations can support better adherence and more positive outcomes. This is especially important for chronic conditions where treatment needs to be sustained over a long period of time. Overall, reducing the burden of treatment can have a significant impact on how well people manage their conditions and improve their overall health.^45,46 Adherence gains are clinically meaningful. Better persistence reduces glycemic variability (in diabetes), flares (in autoimmune conditions), and overall complication rates. For insulin-dependent patients, oral approaches could mitigate the psychological toll of multiple daily injections, fostering a sense of normalcy and control.

6.2 Reduced Risk of Lipohypertrophy and Infection:

Using insulin injections can cause problems right where you get the shot. A lot of people who use insulin for a long time can get something called lipohypertrophy. This is when fat builds up and the tissue gets thicker in the area where they get their shots. It happens to 30-65% of people who use insulin long-term. This can be because they get shots in the same spot over and over, use the same needle too many times, or don't switch up the spot where they get their injections. When this happens, the insulin doesn't get absorbed by the body like it's supposed to, which can cause blood sugar levels to be all over the place. This can lead to more instances of low or high blood sugar, and people might need to take more insulin than they normally would.⁴⁷ By switching to oral delivery, we can completely avoid the risks associated with SC delivery. This means patients no longer have to deal with the challenges of rotating injection sites, tissue damage, and the glycemic instability that can come with it. Infections at injection sites are also less of a concern, although they can still be a problem, especially for patients with weakened immune systems or those who have trouble keeping themselves clean. But with oral delivery, we can bypass the need for skin punctures altogether, which reduces the risk of local infections and eliminates the hazards associated with sharp objects, like needle-stick injuries, for both patients and caregivers. This is a much safer and more convenient option for everyone involved.⁴⁸

6.3 Self-Administration, Dose Flexibility, and User Acceptability:

Oral medications make it easier for people to manage their conditions on their own. With oral forms, you don't need to worry about handling needles or storing devices in the fridge.⁴⁹ This makes them perfect for traveling or everyday life. Plus, oral options can offer more flexibility when it comes to dosing. For example, tablets can be easily adjusted without needing a new prescription, which is a big advantage over other forms of medication.⁵⁰ Overall, oral medications can simplify the process of managing your condition, making it easier to take control of your health.⁵¹ People really like taking medicines that don't involve shots. Lots of surveys have shown that patients prefer taking medicines by mouth rather than getting injections. This is because oral medicines are easy to take, don't have the stigma that injections do, and can be easily added to your daily routine. For instance, when it comes to treating inflammatory or metabolic conditions, patients often prefer oral biologics or peptides because they're more satisfied with them overall. This is especially true for younger patients, those who are afraid of needles, or people who work in jobs where getting injections would be impractical.⁵²

6.4 Pharmacodynamic Profiles and Bioavailability:

SC delivery typically offers high bioavailability (often near 100% for many peptides) and relatively consistent absorption, but with potential variability based on site, temperature, or tissue condition. Oral routes historically faced challenges with gastrointestinal degradation and first-pass metabolism, resulting in lower bioavailability (e.g., ~1% for oral semaglutide vs. SC). However, modern oral formulations can achieve more physiological profiles in certain cases. For insulin, portal vein absorption via the gut mimics endogenous pancreatic secretion more closely than peripheral SC delivery. This can lead to stronger hepatic effects, reduced peripheral hyperinsulinemia, potentially lower hypoglycemia risk, and less weight gain.⁵³ While SC may provide faster or higher peak exposures in some drugs, optimized oral PK/PD can support steady-state control with daily dosing that aligns with natural rhythms. Bioavailability trade-offs are often managed through higher oral doses, but patient-centric benefits (adherence, convenience) frequently outweigh purely numerical PK differences in real-world effectiveness. Head-to-head data for agents like semaglutide show comparable clinical outcomes in many patients, with oral forms offering practical advantages.⁵⁴

6.5 Health Economic and Quality-of-Life Benefits:

From a health economics perspective, non-SC options can reduce direct and indirect costs. Fewer injection supplies, lower complication rates (e.g., lipohypertrophy-related dose increases or ER visits), and improved adherence translate into better disease control and fewer hospitalizations. While oral formulations may require more active pharmaceutical ingredient due to bioavailability, overall system savings arise from reduced healthcare resource utilization, such as training time, device costs, and waste management. People's lives are improved in many ways when they have better treatment options. They feel more free and have less to worry about when it comes to their care. This means they can do their jobs and socialize more easily, and they don't feel as ashamed about their condition. Studies have shown that when people have to take medicine, they prefer to take it by mouth rather than through other means. This is because it's easier and less stressful, which makes them feel better emotionally. When people take their medicine as directed, they tend to have better results in the long run, which also improves their overall quality of life by reducing problems that can come up.⁵⁵

6. Future Directions and Emerging Trends:

Transdermal microneedle (MN) technologies are evolving rapidly from passive delivery platforms to intelligent, responsive systems. These innovations aim to surpass the limitations of subcutaneous injections by offering on-demand, personalized, and closed-loop peptide delivery, particularly for chronic conditions like diabetes. Advances in materials science, electronics, and manufacturing are driving this transformation, with several promising trends poised to reshape peptide therapeutics.⁵⁶

6.1. Smart, Closed-Loop Microneedle Systems:

Here's a rewritten version of the input in a more human-like tone, similar to the provided reference human samples: The development of glucose-responsive microneedle patches marks a significant breakthrough in achieving autonomous control over blood sugar levels. These innovative systems utilize various mechanisms, including phenylboronic acid, enzyme-based triggers like glucose oxidase, or hypoxia-sensitive responses, to release insulin only when glucose levels surge, thereby minimizing the risk of hypoglycemia. Furthermore, dual-hormone patches that can deliver both insulin and glucagon have shown impressive results in preclinical trials involving mice and pigs, demonstrating effective bidirectional regulation. The integration of hollow or hydrogel microneedles with electroosmotic micropumps or iontophoresis enables precise, on-demand dosing, effectively creating a closed-loop system that operates without external intervention. This technology has the potential to revolutionize the management of blood sugar levels, providing a more efficient and reliable means of maintaining glycemic control. By leveraging these advancements, researchers are moving closer to developing a truly autonomous system for regulating blood sugar levels, which could have a profound impact on the lives of individuals living with diabetes.³

6.2. Integration with Wearable Sensors and AI:

The convergence of MN arrays with wearable electronics and artificial intelligence promises highly adaptive therapy.⁵⁷ Graphene-based or electrochemical sensors embedded in MNs can monitor interstitial glucose (or other biomarkers) in real time, feeding data to AI algorithms that predict fluctuations, optimize dosing, and adjust delivery via integrated pumps or stimuli-responsive matrices. Smartphone-powered iontophoretic systems and IoT-connected patches allow remote monitoring and personalized algorithms that account for diet, activity, and circadian rhythms. This integration reduces patient burden while improving outcomes through predictive, rather than reactive, management.^58,59

6.3.3D-Printed Personalized Microneedle Patches:

The way we make things is changing, and this is especially true for medical patches. New technologies like digital light processing and continuous liquid interface production are allowing us to customize these patches quickly. We can make them fit each person's skin perfectly, and even add special features like different needle lengths or separate compartments that release medicine at different times. This is really useful for vaccines and other medicines that need to be delivered in a specific way. Because we can make these patches using 3D printing, we can also make complex designs that help the medicine work better and last longer. Some companies are already using these technologies to make new products, including medicines, vaccines, and even special skin creams. They can make a lot of these patches at once, which is helpful for getting them to people who need them.⁶⁰

6.4. Dual-Hormone and Multi-Peptide Delivery:

Researchers are now looking into using microneedle systems to deliver more than just one type of insulin at a time. For example, they're working on patches that can give you both insulin and glucagon, which can help prevent low blood sugar. They're also trying to create special mixes of peptides that can be used to treat complicated health problems like obesity, autoimmune diseases, or even cancer. These mixes could release different molecules at the same time or one after the other. To make this work, scientists are using special materials like hydrogels or core-shell microneedles, which can release the peptides at different rates. This is important because some peptides are sensitive and need to be protected. It's also a big improvement over traditional injections, which can be hard to coordinate when you need to give someone multiple medications at the same time.²⁷

7. CONCLUSION:

Transdermal microneedle arrays and advanced patches represent a transformative approach to peptide delivery in diabetes management. By effectively bypassing the stratum corneum while minimizing pain and tissue trauma, these technologies offer a compelling alternative to conventional subcutaneous injections for insulin and GLP-1 receptor agonists. Preclinical and early clinical data demonstrate that optimized dissolving, hydrogel-forming, coated, and hybrid microneedle systems can achieve therapeutically relevant bioavailability, favorable pharmacokinetic profiles, and improved glycemic control with significantly enhanced patient comfort and convenience. The benefits for patients are really significant. For one, people are less afraid of needles, and they don't have to deal with lipohypertrophy, which is a big plus. Patients are also more likely to stick to their treatment plans, and their overall quality of life improves. On top of that, there's the potential for a closed-loop system that can deliver insulin in a way that's similar to how the body naturally does it. This can make a huge difference for the nearly 600 million people around the world who are living with this disease. By addressing some of the major challenges that get in the way of successful treatment, we can hopefully improve outcomes for these patients and help them manage their condition more effectively. Nevertheless, important translational challenges remain, including peptide stability, manufacturing scale-up, inter-individual skin variability, immunogenicity concerns, regulatory pathways for drug-device combinations, and cost-effectiveness. As we move forward, combining smart materials, wearable sensors, artificial intelligence, and personalized 3D-printed designs will put microneedle technology at the forefront of treating diabetes with precision. If we keep innovating and have successful trials, systems that deliver peptides through the skin could greatly improve how well patients follow their treatment, their health outcomes, and their overall quality of life. To make this vision a reality, we need ongoing collaboration between researchers, industry experts, regulators, and healthcare providers to turn these promising prototypes into everyday medical practices. This will take time and effort, but it has the potential to make a big difference in the lives of millions of patients. By working together, we can bring these minimally invasive solutions to patients and improve their lives.

8. CONSENT FOR PUBLICATION:

Not applicable. This article does not contain any person’s data in any form.

9. CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

10. ACKNOWLEDGEMENTS:

Authors sincerely acknowledge Rashtriya College of Pharmacy, Hatnoor, Maharashtra, India, for providing support, facilities, and guidance for this research work.

11. REFERENCE:

1. Genitsaridi I, Salpea P, Salim A, Sajjadi SF, Tomic D, James S, et al. 11th edition of the IDF Diabetes Atlas: global, regional, and national diabetes prevalence estimates for 2024 and projections for 2050. Lancet Diabetes Endocrinol 2026; 14: 149–56. https://doi.org/10.1016/S2213-8587(25)00299-2.

2. Zhang Y, Yu J, Kahkoska AR, Wang J, Buse JB, Gu Z. Advances in transdermal insulin delivery. Adv Drug Deliv Rev 2019; 139: 51–70. https://doi.org/10.1016/j.addr.2018.12.006.

3. Chen G, Yu J, Gu Z. Glucose-Responsive Microneedle Patches for Diabetes Treatment. J Diabetes Sci Technol 2019; 13: 41–8. https://doi.org/10.1177/1932296818778607.

4. Ng LC, Gupta M. Transdermal drug delivery systems in diabetes management: A review. Asian J Pharm Sci 2020; 15: 13–25. https://doi.org/10.1016/j.ajps.2019.04.006.

5. Mauldin EA, Peters-Kennedy J. Integumentary System. Jubb Kennedy Palmers Pathol. Domest. Anim. Vol. 1, Elsevier; 2016, p. 509-736.e1. https://doi.org/10.1016/B978-0-7020-5317-7.00006-0.

6. Raina N, Rani R, Thakur VK, Gupta M. New Insights in Topical Drug Delivery for Skin Disorders: From a Nanotechnological Perspective. ACS Omega 2023; 8: 19145–67. https://doi.org/10.1021/acsomega.2c08016.

7. Hong Y, Yu H, Wang L, Chen X, Huang Y, Yang J, et al. Transdermal Insulin Delivery and Microneedles-based Minimally Invasive DeliverySystems. Curr Pharm Des 2022; 28: 3175–93. https://doi.org/10.2174/1381612828666220608130056.

8. Alkilani A, McCrudden MT, Donnelly R. Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the Stratum Corneum. Pharmaceutics 2015; 7: 438–70. https://doi.org/10.3390/pharmaceutics7040438.

9. Shah SWA, Li X, Yuan H, Shen H, Quan S, Pan G, et al. Innovative transdermal drug delivery systems: Benefits, challenges, and emerging application. BMEMat 2025; 3: e70001. https://doi.org/10.1002/bmm2.70001.

10. Trommer H, Neubert RHH. Overcoming the Stratum Corneum: The Modulation of Skin Penetration. Skin Pharmacol Physiol 2006; 19: 106–21. https://doi.org/10.1159/000091978.

11. Bhavsar J, Kasture K, Salvi BV, Shende P. Strategies for transportation of peptides across the skin for treatment of multiple diseases. Ther Deliv 2025; 16: 63–86. https://doi.org/10.1080/20415990.2024.2411943.

12. U. Waghmare S, R. Kudhekar A, H. Sayyad J, B. Yadav D. Enhanced delivery through modified xanthan gum in solid dispersions. Indian Drugs 2026; 63: 29–34. https://doi.org/10.53879/id.63.04.15163.

13. Gattu K, Godugu D, Jain H, Jadhav K, Cho H, Rojekar S. Microneedle Technologies for Drug Delivery: Innovations, Applications, and Commercial Challenges. Micromachines 2026; 17: 102. https://doi.org/10.3390/mi17010102.

14. Moawad F, Pouliot R, Brambilla D. Dissolving microneedles in transdermal drug delivery: A critical analysis of limitations and translation challenges. J Controlled Release 2025; 383: 113794. https://doi.org/10.1016/j.jconrel.2025.113794.

15. Suresh W, Kudhekar A. Healing by Design: Bioactive Hydrogels as Intelligent Tissue Architects. Asian J Pharm Technol 2025: 377–84. https://doi.org/10.52711/2231-5713.2025.00056.

16. Aldawood FK, Andar A, Desai S. A Comprehensive Review of Microneedles: Types, Materials, Processes, Characterizations and Applications. Polymers 2021; 13: 2815. https://doi.org/10.3390/polym13162815.

17. Kim Y-C, Park J-H, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev 2012; 64: 1547–68. https://doi.org/10.1016/j.addr.2012.04.005.

18. Oliveira C, Teixeira JA, Oliveira N, Ferreira S, Botelho CM. Microneedles’ Device: Design, Fabrication, and Applications. Macromol 2024; 4: 320–55. https://doi.org/10.3390/macromol4020019.

19. Sen O, Poddar P, Sarkar P, Das S, Manna S. Current advancements in microneedle technology for therapeutic and biomedical applications. Sens Int 2025; 6: 100325. https://doi.org/10.1016/j.sintl.2024.100325.

20. Tucak A, Sirbubalo M, Hindija L, Rahić O, Hadžiabdić J, Muhamedagić K, et al. Microneedles: Characteristics, Materials, Production Methods and Commercial Development. Micromachines 2020;11:961. https://doi.org/10.3390/mi11110961.

21. Ando D, Miyatsuji M, Sakoda H, Yamamoto E, Miyazaki T, Koide T, et al. Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles. Pharmaceutics 2024; 16: 200. https://doi.org/10.3390/pharmaceutics16020200.

22. Guillot AJ, Cordeiro AS, Donnelly RF, Montesinos MC, Garrigues TM, Melero A. Microneedle-Based Delivery: An Overview of Current Applications and Trends. Pharmaceutics 2020; 12: 569. https://doi.org/10.3390/pharmaceutics12060569.

23. Takehara H, Inada M, Kanda Y, Ichiki T. Mechanical finite element analysis of needle tip shape to develop insertable polymer-based microneedle without plastic deformation. J Mech Behav Biomed Mater 2025; 163: 106885. https://doi.org/10.1016/j.jmbbm.2025.106885.

24. Avcil M, Çelik A. Microneedles in Drug Delivery: Progress and Challenges. Micromachines 2021; 12: 1321. https://doi.org/10.3390/mi12111321.

25. Al-Remawi M, Jaber N, Elsayed A, Alsafadi D, Salah KA. Stabilization of insulin using low molecular weight chitosan carbonate nanocarrier. Carbohydr Polym 2022; 291: 119579. https://doi.org/10.1016/j.carbpol.2022.119579.

26. Yenurkar D, Shrivastava A, Mandal S, Kumar V, Pradhan L, Tripathi S, et al. Development of Emodin Nanocrystal‐Loaded Hydrogel Patch for Rapid Wound Repair. Macromol Biosci 2026;26:e00581. https://doi.org/10.1002/mabi.202500581.

27. Zhao J, Xu G, Yao X, Zhou H, Lyu B, Pei S, et al. Microneedle-based insulin transdermal delivery system: current status and translation challenges. Drug Deliv Transl Res 2022; 12: 2403–27. https://doi.org/10.1007/s13346-021-01077-3.

28. Fan L, Huang J, Ma S. Recent advances in delivery of transdermal nutrients: A review. Exp Dermatol 2024; 33: e14966. https://doi.org/10.1111/exd.14966.

29. Pan X, Zhong Z, Hu X, Wu J, Huang W, Li W, et al. Application of nanotechnology in anti-aging cosmetics: advantages, challenges, and prospects. Polym Bull 2025; 82 :8635–725. https://doi.org/10.1007/s00289-025-05903-3.

30. Kumar A, Kumar D, Kondaveeti SB, Shiekmydeen J, Awasthi A, Singh TG, et al. Polysaccharide-based microneedles for advanced wound healing: recent advances and future challenges. Int J Pharm 2025; 685: 126-256. https://doi.org/10.1016/j.ijpharm.2025.126256.

31. Van Der Maaden K, Sekerdag E, Jiskoot W, Bouwstra J. Impact-Insertion Applicator Improves Reliability of Skin Penetration by Solid Microneedle Arrays. AAPS J 2014;16:681–4. https://doi.org/10.1208/s12248-014-9606-7.

32. Zhang N, Zhou X, Liu L, Zhao L, Xie H, Yang Z. Dissolving Polymer Microneedles for Transdermal Delivery of Insulin. Front Pharmacol 2021;12:719905. https://doi.org/10.3389/fphar.2021.719905.

33. Sun T, Dasgupta A, Zhao Z, Nurunnabi M, Mitragotri S. Physical triggering strategies for drug delivery. Adv Drug Deliv Rev 2020;158:36–62. https://doi.org/10.1016/j.addr.2020.06.010.

34. Tari K, Khamoushian S, Madrakian T, Afkhami A, Łos MJ, Ghoorchian A, et al. Controlled Transdermal Iontophoresis of Insulin from Water-Soluble Polypyrrole Nanoparticles: An In Vitro Study. Int J Mol Sci 2021;22:12479. https://doi.org/10.3390/ijms222212479.

35. Opatha SAT, Titapiwatanakun V, Chutoprapat R. Transfersomes: A Promising Nanoencapsulation Technique for Transdermal Drug Delivery. Pharmaceutics 2020; 12:855. https://doi.org/10.3390/pharmaceutics12090855.

36. S.U W, Mishra A, S.G K. Recent Advances in Polymeric Microparticles - Based Drug Delivery Systems for the Treatment of Diabetes. Res J Pharm Technol 2025: 1611–8. https://doi.org/10.52711/0974-360X.2025.00231.

37. Serrano DR, Juste F, Anaya BJ, Ramirez BI, Sánchez-Guirales SA, Quispillo JM, et al. Exosome-Based Drug Delivery: A Next-Generation Platform for Cancer, Infection, Neurological and Immunological Diseases, Gene Therapy and Regenerative Medicine. Pharmaceutics 2025; 17: 1336. https://doi.org/10.3390/pharmaceutics17101336.

38. Wu C, Zong Z, Hua F, Wu J, Shen Y, Tian Y, et al. Advances in Microneedle Drug Delivery for Obesity: Mechanisms, Applications, and Perspectives. Int J Nanomedicine. 2025; 20: 15213–34. https://doi.org/10.2147/IJN.S566132.

39. Shelke PS, U W, Rk S, Pawar TB, Bhingar HR, Narode PA. A review on solubility enhancement technique. Int J Pharm Pharm Sci 2024; 6:144–8. https://doi.org/10.33545/26647222.2024.v6.i1b.113.

40. Mdanda S, Ubanako P, Kondiah PPD, Kumar P, Choonara YE. Recent Advances in Microneedle Platforms for Transdermal Drug Delivery Technologies. Polymers. 2021; 13: 2405. https://doi.org/10.3390/polym13152405.

41. Sasaki GH. The Significance of Trans-Epidermal Water Loss After Microneedling and Microneedling-Radiofrequency Procedures: Histological and IRB-Approved Safety Study. Aesthetic Surg J Open Forum. 2019; 1: ojz017. https://doi.org/10.1093/asjof/ojz017.

42. Liu Q, Ranallo R, Rios C, Grice EA, Moon K, Gallo RL. Crosstalk between skin microbiota and immune system in health and disease. Nat Immunol. 2023; 24: 895–8. https://doi.org/10.1038/s41590-023-01500-6.

43. Zhang E, Zhu H, Song B, Shi Y, Cao Z. Recent advances in oral insulin delivery technologies. J Controlled Release. 2024; 366: 221–30. https://doi.org/10.1016/j.jconrel.2023.12.045.

44. Alsbrooks K, Hoerauf K. Prevalence, causes, impacts, and management of needle phobia: An international survey of a general adult population. PLOS ONE. 2022; 17: e0276814. https://doi.org/10.1371/journal.pone.0276814.

45. Isaacs DM, Kruger DF, Spollett GR. Optimizing Therapeutic Outcomes with Oral Semaglutide: A Patient-Centered Approach. Diabetes Spectr. 2021; 34: 7–19. https://doi.org/10.2337/ds20-0016.

46. Karedath J, Nall S, Kaur M, Lokhandwala A, Aqel YH, Maali Abusal A, et al. Comparative Effectiveness and Safety of Oral Versus Subcutaneous Semaglutide in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Cureus. 2025. https://doi.org/10.7759/cureus.82497.

47. Nain RA, Thomas DC. Lipohypertrophy prevalence and its associated risk factors in insulin-treated patients with type 2 diabetes in North Borneo, Malaysia. Belitung Nurs J. 2022; 8: 521–8. https://doi.org/10.33546/bnj.2246.

48. Abdel‐Moneim A, Ramadan H. Novel strategies to oral delivery of insulin: Current progress of nanocarriers for diabetes management. Drug Dev Res 2022; 83: 301–16. https://doi.org/10.1002/ddr.21903.

49. Mishra A, Waghamare S, Khanage SG. Acarbose-Loaded PLGA Microspheres: Efficient Encapsulation and Controlled Release. J Drug Deliv Ther. 2025; 15: 30–40. https://doi.org/10.22270/jddt.v15i6.7165.

50. Chavan T, Waghamare S, Kokare S, Madake A. Advanced Treatment of Type 1 Diabetes with Teplizumab: Mechanism and Clinical Efficacy. Asian J Med Princ Clin Pract. 2025; 8: 1–11. https://doi.org/10.9734/ajmpcp/2025/v8i1262.

51. Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ. Advances in Oral Drug Delivery. Front Pharmacol 2021;12:618411. https://doi.org/10.3389/fphar.2021.618411.

52. Myers J, Van Dam J, Imran M, Hashim M, Dhalla A. Preference for a Novel Oral Alternative to Parenterally Administered Medications. Patient Prefer Adherence. 2024; 18: 1547–62. https://doi.org/10.2147/PPA.S463354.

53. Adepu S, Ramakrishna S. Controlled Drug Delivery Systems: Current Status and Future Directions. Molecules 2021;26:5905. https://doi.org/10.3390/molecules26195905.

54. Meier JJ. Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation. Front Endocrinol 2021; 12: 645617. https://doi.org/10.3389/fendo.2021.645617.

55. Boye K, Ross M, Mody R, Konig M, Gelhorn H. Patients’ preferences for once‐daily oral versus once‐weekly injectable diabetes medications: The Revise study. Diabetes Obes Metab. 2021; 23: 508–19. https://doi.org/10.1111/dom.14244.

56. Waghamare S, Jahed S, Kudhekar A, Patil P, Nikam P. Foundations of Artificial Intelligence in Pharmaceutical Preformulation. In: Waghamare S, Gaikwad A, Jahed S, Khanage S, editors. Artif. Intell. Preformulation Stud. Predict. Methods Mod. Pharm. Dev. Deep Science Publishing; 2026. https://doi.org/10.70593/978-93-7185-262-3_1.

57. Waghamare S, Gaikwad A, Jahed S, Khanage S, editors. Artificial Intelligence in Preformulation Studies: Predictive Methods For Modern Pharmaceutical Development. Deep Science Publishing; 2026. https://doi.org/10.70593/978-93-7185-262-3.

58. Gupta M, Srivastava N, Rai AK, Kathuria H. Recent advances in microneedles for drug delivery and theranostic application. Eur Polym J. 2025; 228: 113773. https://doi.org/10.1016/j.eurpolymj.2025.113773.

59. Kudhekar A, Waghamare S, Kadag P. Smart Separation Techniques: AI-Based Optimization in the Formulation Process. In: Waghamare S, Gaikwad A, Jahed S, Khanage S, editors. Artif. Intell. Preformulation Stud. Predict. Methods Mod. Pharm. Dev., Deep Science Publishing; 2026. https://doi.org/10.70593/978-93-7185-262-3_4.

60. Bernatoniene J, Stabrauskiene J, Kazlauskaite JA, Bernatonyte U, Kopustinskiene DM. The Future of Medicine: How 3D Printing Is Transforming Pharmaceuticals. Pharmaceutics 2025; 17: 390. https://doi.org/10.3390/pharmaceutics17030390.

Received on 24.05.2026 Revised on 13.06.2026

Accepted on 27.06.2026 Published on 07.07.2026

Available online from July 10, 2026

Res. J. Pharma. Dosage Forms and Tech.2026; 18(3):255-264.

DOI: 10.52711/0975-4377.2026.00037

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.