Department of pharmaceutics, Arvind Gavali College of Pharmacy Jaitapur, Satara 415004, Maharashtra, India.
Among the many benefits of the MNs-based system are its low cost, excellent medical efficacy, relative safety, and painless drug application. An overview of studies conducted in MNs on the transdermal delivery of medications for hypertension is given in this review article. The pharmacokinetics, manufacturing techniques, and drug release mechanism, applications in medicine, a future difficulties are some of the crucial characteristics of micro needles that are covered. This targeted review opens the door for future pharmaceutical applications by giving a summary of published research and the latest developments in MN-based provision of hypertensive provision of medicine. MN-based medication transport has become more crucial for systemic therapy since it avoids first-pass metabolism as well as the wide range of levels of drug plasma. To sum up, MN-based medication delivery for hypertensive medications to improve bioavailability and patient adherence may help fuel a new hypertensive trend. Among the many benefits of the MNs-based system are its low cost, excellent medical efficacy, relative safety, and painless drug application.
A pathological condition known as hypertension (HTN) is typified by raised blood pressure (BP), with a systolic reading of 140–150 or higher [1]. With around 9 million fatalities annually, hypertension is among the world's primary causes of death and illness, The World Health Organisation claims that (WHO) [2]. Numerous conditions, including heart failure and cardiovascular illness Atrial fibrillation, angina pectoris, diabetes mellitus, and chronic kidney disease (CKD) are all believed to be strongly impacted by hypertension [4,5]. Hypertension are believed to often coexist have been related to high blood pressure (BP) in extensive scientific research [3]. Chronic kidney disease (CKD), diabetes mellitus, and atrial fibrillation and angina pectoris are all thought to be significantly influenced by hypertension [4,5]. According to some published research especially beta-blockers, appear increase the risk a diabetes in those with hypertension [6]. In addition, antihypertensive medication can significantly lower the heightened risk associated with high blood pressure by lowering blood pressure as well as the related target injury to the organs [7, 8]. The initial line of treatment for hypertension may involve the use of calcium channel blockers (CCBs), thiazide-type diuretics, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACE inhibitors). All antihypertensive classes reduce the risk of cardiovascular events [9]. It can be challenging for people with hypertension to follow their medication regimens when using traditional dosage forms such tablets, capsules, and injections. [10]. Children with hypertension have needle allergies and difficulty swallowing [5]. The majority of antihypertensive medications are administered as tablets; nevertheless, tablets have a number of drawbacks, such as gastrointestinal distress, stomach drug breakdown, uneven absorption, and pre-systemic drug metabolism, which ultimately results in decreased bioavailability [10, 11]. By using Drug delivery systems based on transdermal micro needles (MN) to dispense antihypertensive medications, such problems can be somewhat resolved [12]. The transdermal medicine delivery device based in Minnesota circumvents limitations of the injectable and oral methods because The needles don't cause any harm., inexpensive, simple to apply [13–16]. These needles, which are less than 1000 µm, can readily pass past the main epidermal barriers that prevent drug molecules from entering the stratum corneum painlessly. [15, 17]. Because MN systems are easy to administer and have improved biodistribution and efficacy, they can deliver accurate drug localisation with fewer doses and increase patient compliance [18]. The poor water solubility of antihypertensive drugs is a major issue for their therapeutic use.
Anatomy And Physiology:
Three separate yet interdependent tissues make up human skin.
A) Cellular, vascular, stratified epidermis;
B) Connective tissue the dermis beneath; and
C) The layer beneath the skin
Fig No-1: Anatomy And Physiology of Skin
The SkinThe thickness of the multi-layered epidermis varies from 0.8 mm on the palms and soles to 0.06 mm on the eyelids, depending on the size of the cells and the number of cell layers. Thickness, diffusivity, and water permeability through the epidermis. It is made up of the viable epidermis and the outer stratum corneum.
The corneum stratum
The skin's outermost layer is this one sometimes referred to Horney layered. When completely hydrated, it swells to several times its dry thickness of around 10µm. It has between 10 and 25 corneocyte layers, which are dead, keratinised cell. Despite its flexibility, it’s not very porous. The main obstacle to drug penetration is the stratum corneum. One way to model the Horney Layer's design is like the framework of a wall. The keratinised cells function as "bricks" of protein." encased in lipid "mortar" in this paradigm. The lipid fraction contains enough amphiphilic material, such as polar free fatty acids and cholesterol, in order to maintain a bilayer shape.
Thriving epidermis
They vary in thickness. They are situated below the stratum of corneum. And vary in size between 0.8 mm on the palms to 0.06 mm on the eyelids. The layers that comprise the interior include the stratum spinosum, stratum lucidum, and stratum granulosum stratum basal. Mitosis, which also makes up for the death of Horney cells from the epidermis, allows the epidermis to continuously regenerate at the bottom layer by cell. The cells produced by the basal layer undergo morphological and histological changes as they move outside, going through keratinisation to form the stratum corneum's outermost layer.
The dermis
The dermis is a 3–5 mm thick layer of connective tissue matrix and nerves.
Both the blood vessels and lymphatic. Controlling body temperature is one of the cutaneous blood supply's most important functions. It provides the skin with oxygen and nutrients in addition to removing waste and pollutants. The majority of molecules that penetrate the skin barrier find sink conditions in capillaries, which are located within 0.2 mm of the skin's surface. Consequently, the blood supply maintains a very low dermal concentration of a permeant, and transdermal penetration is dependent on the concentration gradient that develops across the epidermis.
The layer that lies beneath the skin
The dermis and epidermis are supported by the hypodermis, or subcutaneous fat tissue. It acts as a place to store fat. This layer offers mechanical protection, nutritional support, and temperature management. It may have sensory pressure organs and transports the skin's main blood vessels and nerves.
The Pathway Of Infiltration [7-9]
Chemicals diffuse passively via the skin. Is a component a percutaneous absorption? The appendageal and epidermal diffusional routes are the two ways a molecule can pass through healthy, intact skin.
Path of the appendix
The path of the appendages includes transportation by means of sebaceous glands that are connected to sweat glands and hair follicles. These paths are Also known as "shunt" routes because they avoid penetrating the stratum corneum. Due to its comparatively modest the area (about 0.1 percent of the entire skin surface), this pathway is regarded as having little significance.
Epidermal route: The Trans cellular (intracellular) and intercellular pathways are two possible microroutes of entry for medications that primarily penetrate the intact Horney layer.
i) Transcellular: A transcellular pathway is the movement of chemicals over the cellular membrane of an epithelial cell. These include Macromolecule endocytosis and transcytosis, active transportation of polar and ionic substances, and passive transport of tiny molecules.
ii) Paracellular: A paracellular pathway is a way for chemicals to move between or inside cells. There are close ties or similar circumstances in between the cells. The partition coefficient (log k) primarily determines the predominant pathway that a permeant takes. While lipophilic permeates pass through the stratum corneum through the intercellular pathway, hydrophilic medicines preferentially partition into the domains inside cells. The majority of permeates enter the stratum corneum through both pathways. Nonetheless, it is generally accepted that the main mechanism and significant obstacle to the majority of medications' penetration is the convoluted intercellular pathway.
Fig No-2: Permeation pathway
Characteristics That Affect the Transport of Drugs Via the Skin (10–11)
Three aspects can be taken into consideration when formulating an effective transdermal medication delivery strategy. There are two categories of elements that influence this: physicochemical factors and biological factors.
Skin condition: an abundance of solvents, including methanol and a chloroform, as well as acids and alkalis, cause damage to skin cells and promote penetration. Skin conditions shift when a patient is ill. Although healthy skin provides a better barrier, penetration is impacted by the for mentioned factors.
B. Elements of
Physiochemistry
Hydration: When water comes into contact with the skin, its permeability rises noticeably. The most crucial component for improving skin penetration is hydration. The use of humectants topically.
PH and temperature: When pH changes, the amount of medication that permeates increases tenfold. As the temperature increases, the diffusion coefficient decreases. The dissociation of weak acids and weak bases is determined by the pH and pKa or pKb values. The fraction of unionised drug determines the drug concentration in the skin. Therefore, two important factors affecting drug penetration are temperature and pH.
Diffusion coefficient: The drug's penetration is determined by its diffusion coefficient. The drug's diffusion coefficient at a fixed temperature is determined by the properties of the drug, the diffusion medium, and their interactions.
Drug concentration: The flow is regulated by the concentration gradient across the barrier, and a higher drug concentration across the barrier will result in a bigger concentration gradient.
Partition coefficient: Good action requires the ideal partition coefficient (K). High-K drugs are not yet ready to exit the skin's lipid layer. Moreover, medications with low K levels are unable to
Molecular shape and size: Smaller molecules absorb drugs more quickly than larger ones, and drug absorption is negatively correlated with molecular weight.
Optimal Molecular Characteristics for Transdermal Medication Administration
We can draw certain conclusions from the aforementioned considerations that might be referred to as the optimum molecular characteristics for medication penetration. They are listed below.
1. A sufficient solubility in water and lipids is required for improved medication penetration (1 mg/ml).
2. A good therapeutic effect requires an optimal partition coefficient.
3. The saturated solution's pH should range from 5 to 9.
Techniques Used to Improve Permeability:
The penetration of active molecules through the skin is a drawback of transdermal administration. As a result, numerous investigations are conducted to increase its permeability using percutaneous means.
Three mechanisms are used by them to act:
(1) By altering the corneum stratum's physicochemical qualities.
(2) By modifying the corneum stratum's hydrating characteristic.
(3) Through a mechanism of the carrier that modifies structure of proteins & lipids in the channel between cells (19).
Vehicle/drug interaction
Selection of drugs and prodrugs it’s crucial to carefully choose the active ingredient according to Its pharmacological or physiochemical characteristics.
The following characteristics are ideal for drug selection:
Ion-pair
Despite being a charged molecule, active moiety, which can enter the skin, is impermeable. The lipophilic ion pair approach, however, can improve penetration into the epidermis. This method creates a pair of oppositely charged species that dissociate in living water-based epidermis and realise parent molecules, as well as neutralise the charge (21). As it separates or disperses and acts similar to a pair of ions, the coacervate penetrates the skin (22). The impact of ion pairing on lignocaine penetration is determined by Valenta et al. Polydimethylsiloxane (PDMS) was used for diffusion investigations at pH values of 4.0, 6.0, 7.0, and 8.0. Several counter ions were used to boost up to 2.45 times the steady state lignocaine flux. According to measurements, lignocaine morpholinopropanesulfonate (L-mps) had the maximum flux (23). Riserdronate is used to treat a variety of bone problems because it inhibits osteoclastic activity. Its limited skin penetration is caused by its strong ionisation and high acidity found an L-arginine-containing ion-paired solution that was evaluated on a mouse without hair in vitro. Between 14.13 ± 5.49 mg/cm2 (24), the flow increased 36 times to 475.18 ± 94.19 g/cm2 and 511.21 ± 106.52 g/cm2.
Eutecticblends
Skin penetration is directly impacted by a substance's solubility, which is mostly determined by its melting point. Solubility in skin lipids increases with decreasing melting point (25). We create eutectic mixes, which are mixtures of two components that inhibit the crystalline phase at a specific ratio, in order to reduce the higher melting point. In this manner, the two components' melting points are lower than the single component's (26). For instance, lignocaine with menthol, ibuprofen with terpenes, propranolol with fatty acids, and menthol with methyl nicotine. Because of their gastrointestinal adverse effects, analgesics like NSAIDs are best taken topically, particularly for local discomfort. Using thymol as a penetration enhancer, a meloxicam transdermal formulation distribution was designed. Meloxicam is one of the NSAIDs that does not currently have a topical version on the market (27). According to in vitro permeation tests, the guinea pig's maximal flow, or 22.06 mg/cm2, is at a ratio of 5.5 (meloxicam: thymol) (27).
Modification Of the Horny Layer
Drinking plenty of water
The most effective approach for both hydrophilic and hydrophobic medications to penetrate is through water. The stratum corneum has a concentration of 10–20% under normal circumstances. Enhancing permeability requires the epidermis to be hydrated. Using this method, Skin immersed with water can quickly absorb a substantial volume of water. The hygroscopic feature of corneum is mediated by Natural Moisturizing Factor (NMF). Salts and free amino acids make up the majority of it. Hydration of the skin results in keratin swelling, alters lipid packing, and disrupts polar and non-polar pathways (28).
Enhancer of chemicals
Chemical enhancers aid in skin penetration by interfering with intercellular proteins, disrupting the stratum corenum lipid's highly organised structure, or improving the drug's partition into the stratum corneum (29). The following qualities are desirable in chemical enhancers:
1. Non-toxic and non-allergic.
2. Its duration should be predictable and its working activity should be quick (29).
3. It ought to be one-way. Its suitability for both medications and excipients.
Qualities in accordance with the Cosmetics and Drugs Act (30).
Fig No-3: Various Strategies Increase Penetration
Microneedle Array
Fig No-4: Micro Needle Array
MNs are medical devices that deliver medication elements of the skin's outermost layers using one or a collection of needles with a diameter of a few micrometres [31, 32]. A needle up to 1000 µm long is sufficient for transdermal drug delivery since it can penetrate the corneum layer and discharge the medication within the dermis [33, 34]. MNs gain from lowering stress or fear brought on by vasovagal reactions, Fear of needles, and suffering while using a conventional a needle [35, 36]. MNs are produced of variety of materials, such as glass, metal, & silicon. The forms of the needles may vary from square pyramids to cones, depending on the manufacturing process [37]. MNs must have sufficient strength to puncture the skin without causing haemorrhage [38]. The MNs should ideally break down in the human skin to liberate the confined pharmacological cargo and avoid sharp waste [39]. MNs are superior to oral and other drug administration modalities because of their special qualities and Steer clear of sharps and dangerous waste [40,41]. This technique would be useful for swallowing difficulties in children and elderly people [40]. A variety of MNs can be categorised based on the intended drug delivery method, including metal MNs, coated MNs, sugar MNs, hollow MNs, solid MNs, dissolving MNs, polymer MNs, glass MNs, hydrogel forming MNs, ceramic MNs, and silicon MNs [42–49]. The majority of MNs were constructed of silicon in the early stages of development [50]. Certain metals, including as nickel, stainless steel, titanium, and other materials, offer well-integrated The mechanical properties, like high durability and strength, that can shield protection of MNs from mechanical failure. Moreover, the cost of producing metal MNs is less than that of silicon MNs. Bio hazardous tip debris will also be produced by metal MNs [51]. Polymers are the most promising materials for production in Minnesota. They can have advanced characteristics, including integrated controlled release mechanisms, and be versatile, affordable, readily available, and biocompatible [48]. Because polymers are more resilient than brittle materials like silicon, polymer MNs can avoid brittle fracture when they are inserted into the skin. Since most polymers don't have serious negative effects, polymer MNs rarely are compatible with the body. Please take aware that a Micromolding is one of the manufacturing techniques appropriate for producing MNs in large quantities at a moderate cost. Due to the low melting temperature of the majority of polymers. Polymers are therefore becoming more and more well-liked and are thought to be promising materials for MN manufacture [51]. Over the previous forty years, Minnesota technology has continuously improved. MNs have been shown to carry several preclinical studies and a limited number of clinical trials involving the administration of vaccinations, insulin, and other pharmacological dosage forms through the skin [52].
Classification Of Microneedle-
Fig No-5: Classification Of Micro Needle
Type Of Microneedle-
Hollow micro needles
A variety of micron-sized hypodermic needles known as hollow micro needles (HM) are used to administer a variety of medicinal substances [53]. For instance, Pre-loaded insulin in such HM might offer a rapid and simple way to administer insulin for type 1 diabetes in place of a traditional hypodermic needle, which could cause unanticipated trypanophobia or dangerous infections during injection. Davis et al. showed that hollow metal micro needles might provide an insulin dosage for diabetes that is physiologically appropriate [54]. In this investigation, 50 mU of insulin given via a traditional hypothermic needle had the same pharmacokinetics as a single nickel-coated titanium-copper-titanium metal HM with a sharp, hollowed, and funnel-like form in hairless diabetic rats. Furthermore, certain improved geometric properties of HMs have been investigated [55, 56]. Out-of-plane figures, in which the needles are arranged perpendicularly in a two-dimensional array, have been proposed as an alternative to in-plane HMs. HMs can reduce the risk of clogging when administered through the skin while providing the necessary drug exposure through the needles and barrel sidewalls due to their two potential opening sites at the Out-of-plan. Anisotropic wet etching, deep-reactive ion etching, and conformal thin film deposition were among the production techniques utilised in investigation to show an out-of-plane HM with varying tip curvatures. Similarly, continuous isotropic and anisotropic etching was used to create silicone HM coated in titanium and gold with tapered points [57].According to this study, the silicone base had an outer diameter of 160 µm, and the tapered tips in the silicone HM array were made with 130 µm thanks to the isotropic etch. The silicone HMs were then made implantable by applying titanium and gold coatings. Due to their coating of these metals, the silicone HM was approximately ten times more resistant to breaking under pressure than the skin. However, older HM designs require costly and sophisticated instruments in several production processes. The more useful option for producing hollow needles with comparatively easy solvent casting techniques is to use polymeric HMs. When the polymer dried, Mansour et al. produced strong polymeric micro needles using a spin-coated clay-reinforced polyimide on an SU-8 pillar mould constructed on a 300 µm thick Pyrex glass substrate [56]. Next, the writers created apertures at the tip using sanding or plasma etching procedures. Despite the simplicity of this polymer-based approach, the polymeric HMs demonstrated enough mechanical strength to be inserted through the skin. There are two distinct HMs in the market. Drugs are administered by a hollow array of stainless steel micro needles in the AdminPen® syringe (Nano biosciences, LLC., Sunnyvale, CA, USA) [58]. Depending on the company's requirements, the MN might range in length from 600 to 1500 µm.As a result, applying it could be little painful. Regardless of the respondents' level of pain, a study examining the association between normalised pain levels and the lengths of micro needles (480, 700, 960, and 1450 µm) revealed that greater MN lengths progressively increased pain scores [59]. The authors found that when the 26-gage hypodermic needle's discomfort was given a 100% score, a threefold increase in MN lengths causes the pain scores to increase sevenfold, from 5% to 37%. A glass cartridge and uniformly spaced micro needles make up the HM array of the 3M Hollow Microstructure Transdermal System (hMTS), another commercial HM [60].
Fig No-6: Hollow Micro Needles
Solid Micro Needles
Because the applied MN immediately creates micro channels, high molecular weight drugs can be delivered in this type of MN. For a certain amount of time, a solid MN increases the permeability of the skin by creating numerous micro channels on its surface using the array of solid MN. But when the skin's natural healing processes take hold, the resulting micro channels can vanish. Consequently, there is no second chance for the solid MN of contracting dangerous infectious diseases in healthy skin. Self-healing following insertion has been extensively reported in an intriguing study. Several metal needles of varying lengths, thicknesses, and widths have been used to study the healing of the damaged epidermal barrier after implantation [61]. This study also demonstrated that the primary cause of the skin barrier's healing delays is occlusion. Therefore, it is anticipated that the skin barrier will be restored more easily if the solid MN is detached after use [61]. A 20 x 20 solid MN array with needles that are 150 µm long and sharp was employed in a study conducted in early 1998 to move the fluorescein molecule calcein through the human skin [62]. According to the study, these silicone-based solid MNs were able to effectively transmit the low molecular weight material into the skin's subcutaneous layers by leveraging the pores they produced. In a similar vein, a study discovered that the micro channels made possible by micro needling enabled the efficient administration of insulin, hence lowering the increased blood glucose levels in diabetic rats [63]. This study also showed that for transdermal insulin administration, micro needling works just as well as traditional needle injection. A solid MN containing naltrexone (NTX) is another form of medication administration used to treat alcohol and opiate addictions [64]. In contrast to the conventional NTX patch, this solid MN maintained a steady-state drug plasma concentration for 48 hours while providing NTX for 72 hours. According to this study, in human volunteers given 25 mg of heroin intravenously, NTX concentrations greater than 2 mg/mL corresponded with an 85.6% narcotic blockade 48 hours after patching. As mentioned earlier, the small micro channel pores allow the solid MNs to readily transport therapeutic chemicals. However, the drug's physicochemical properties determine how effective this transdermal delivery is. The degree of drug penetration into the SC is determined by factors such as the drug's melting point, permeability coefficient, partition coefficient, and molecular weight. This implies that transdermal delivery systems based on micro needles are likewise subject to the main principles of skin penetration.
Fig No-7: Solid Micro Needles
Types Of Microneedles for Function
1. Micro needle Dissolution:
This type of MN has garnered a lot of attention due to the user-friendly "poke and release" idea that dissolving micro needles offer [65,66]. Nonetheless, polysaccharides or other polymers are typically used to make these needles to dissolve the entire section of the MN. The most common method for creating dissolving MNs is to pour the polymeric solutions into moulds and let them cure at room temperature under vacuum. The medicinal ingredients are combined and dried together prior to the application of the polymeric solution. Utilising the dissolving MN, the medicinal ingredients gradually penetrate the skin and break it down through a process of swelling or dehydration. The main benefit of this kind of MN is that it may deliver the agent in a single application without blocking the micro channels, which prevents them from drying out completely.
2. Micro needles with coatings:
Coated MNs can apply desired pharmaceuticals to the surface of each pillar of the created micro needles instead of loading the medication in producing MNs [67]. Drug-containing dispersions can cause the coated needles in the micro needle array to release subcutaneously [67]. Since this method can use many proven coating techniques elsewhere, a variety of fabrication techniques have been investigated. These include electro hydrodynamic atomisation (EHDA), dip coating, gas-jet drying, spray drying, and piezoelectric inkjet printing [68]. Dip-coating is the simplest method, which entails dipping the micro needles in a medication-containing solution and then removing them. The surface of the micro needles can also be repeatedly dip-coated to create a drug-loaded thin film of varying thickness. For easy transdermal delivery, a variety of biomolecules, such as proteins, viruses, and DNA, have been dip-coated onto micro needles [69]. But during the slow drying phase, the dip-coating also produces a rounded micro needle. Each micro needle’s barrel and array tip have an irregular, spherical coating made of the dry film. One solution to this issue is gas-jet drying [70]. With this technique, A medicinal substance can be uniformly applied to the micro needles' the surface since the agents travel through the transitional gas phase when they are coated by a gas-jet applicator. In order to eliminate the possibility of solution run-off, which is observed with the dip-coating technique, the way to solve this is usually prepared to have optimal Properties of surface tension and viscosity. This enables the solution to be coated on the micro needle surface quickly and evenly [70]. Similarly, we can apply a thin, consistent layer to the micro needle using the spray coating technique. This procedure involves quickly applying atomised droplets of the therapeutic-containing solution to the micro needle surfaces for deposit, followed by surface drying to produce an equal layer [71]. The atomised droplets in the EHDA-based approach are additionally exposed to accelerate their transit through a capillary nozzle by applying an electrical field. The drop in motion can then be positioned beneath the nozzle tip on the electrically grounded micro needle [72]. In contrast to other coating methods, the EHDA-based approach uses an extra surface-insulated mask to coating the sole final MN's advice. Since the liquid used in this process needs to have the right amount of surface tension, it is typically a polymeric solution with a solvent.
Use: Clinical Implementation Of MNS
The functionality, stability, and safety of commercially produced MN arrays and customised MN patches for intradermal distribution have been the subject of several preclinical studies and clinical trials in recent years. Based on clinical trials found at www.clinicaltrials.gov.us, the suggested MNs were assessed for skin disorders, local anaesthesia, vaccine distribution, glucose monitoring, and bio sensing applications. In a clinical trial investigation, the systemic contents of glucose in both type 1 diabetes patients and healthy volunteers were continuously monitored using solid MN array-based sensors based on interstitial glucose levels. A minimally intrusive technique was also employed to detect the residue of particular chemicals, like beta-lactam antibiotics, based on the results reported. Compared to extracting interstitial fluids, it was proposed that putting MN patches on the exterior of cutaneous tissue is a less intrusive and straightforward method of sample collection. The calibre of samples taken with MN patches in comparison to the traditional skin biopsy method was examined in a recent clinical trial research Regarding RNA sequencing. However, the outcomes have not yet been reported. Evidence suggests that MN patches are suitable for immunising people against a range of infectious diseases, including influenza, foodborne illness, rubella, and more. These claims are supported by the successful administration of insulin to diabetic patients through hollow MNs. It is important to note, in light of recent research, that MN patches with different geometrical values and designs are a suitable delivery strategy for treating a wide range of clinical conditions. Furthermore, MN patches can be created by integrating many scientific fields in a way that minimises cutaneous tissue invasion for bio sensing, sampling, releasing, and monitoring applications. Notably, using MN patches for topical administration appears to be a very good option and can help prevent the negative effects of systemic administration of several medicinal substances.
Fig No-8: Clinical Implementation of MNS
MNs' benefits for drug delivery
Transdermal patch needs the medication to pass through the stratum corneum barrier, its bioavailability is reduced. By adding the transdermal patch can act as a permeability enhancer by somewhat increase drug penetration. The dermis is deeply penetrated by the hypodermic needle, which contains pain receptors. Because it hurts, patients are less likely to comply, even though it can deliver 90–100% of the loaded medicine. MNs release 100% of the loaded medicine painlessly by avoiding the stratum corneum barrier and entering the dermal and epidermal layers directly.
Prospects For Microneedling and Microneedles in The Future
Even in chronic cases, skin disorders are likely to be cured or managed with the use of treatments with MN assistance and micro needling for a variety of the skin issues, encompassing skin cancer. Drug-eluting methods (coated and dissolving MNs) and major MNs (solid and hollow) were studied here. The practical applications of MN-supported clinical approaches and micro needling, particularly for skin and PDT malignancies, were then examined. As mentioned, numerous emerging new strategies that use MN and other pharmaceutical technologies to create a new therapeutic modality with the purpose of treating complex diseases (like melanoma). For instance the authors can use thermo responsive lanthanum hex boride nanostructures that are already incorporated in polycaprolactone MN to precisely unload chosen medications into the inner region of the skin using near-infrared (NIR) light [73]. When activated by an NIR light, the thermo responsive nanostructures can increase Minnesota's temperature by up to 50 °C. Light-to-heat-mediated transduction may help us create an on-demand MN-assisted method to treat a range of skin-related conditions. According to the most common precancerous associated with photo damaged skin, micro needle-mediated photodynamic therapy (PDT) has been shown to be effective in increasing actinic keratosis by enhancing the penetration of aminolevulinic acid (ALA) as a photosensitized [74]. Since both technologies may provide therapeutic medicines with a minimal risk of metabolic drug clearance, provide targeted drug delivery, and enable self-administration of pharmaceuticals, such combinational tactics would be more actively studied in the future. Even while MN materials have advanced significantly, there are still some obstacles to overcome. Individual differences in adverse effects, such as skin redness, irritation, or allergy, still happen even though micro needling and micro needle-assisted transdermal administration are minimally invasive techniques. Furthermore, because there is a very little amount of loadable medication per MN patch, numerous MN patch administrations would be required if a specific indication requires a high dosage to be cured. Such frequent use of MN may lead to secondary problems such as impaired skin barriers, hypersensitivity skin reactions, and an increased risk of infection. Regarding this, a study demonstrating that the mean micro pore closure period after MN treatment (fifty stainless needles with an 800 µm length) of roughly 60 hours would provide a clue for future research, regardless of the anatomical locations (upper arm, volar forearm, and abdomen) [75]. Supporting the medical industry may depend on the creation of novel self-healing Minnesota materials that hasten wound healing.
|
Sr .No |
MN Type |
Characteristic & Method Of Delivery |
Advantage |
Disadvantage |
Application |
Material |
|
1 |
Hollow Micro needle |
Controls drug release by using time pressure to drive the flow through the needle. |
Enables high drug doses with precise control of flow rate and dose accuracy. Easy to formulate and supports hydrophilic behaviour for drug delivery |
Complex design requiring durable materials and careful engineering to avoid clogging. Prone to blockage in narrow channels and challenges with prefilled syringes. |
Disease diagnosis |
Silicon. |
|
2 |
Coated Micro needle |
Delivers a low dose of encapsulated drug through coating drug release. |
Rapid delivery through the skin, stability of drug, and enhanced permeability due to potent formulations. Provides mechanical strength. |
Risks of infection and drug loss during fabrication. Expensive to manufacture and can irritate if needles are damaged. |
Drug and vaccine delivery. |
Silicon. |
|
3 |
Solid Micro needle |
Creates channels in the skin to improve drug permeability using sharper tips with strong mechanical strength. |
Suitable for a wide range of drugs. Improves permeability and can use various materials for formulation. |
Requires stitching up after use to prevent infection. Restricted drug surface area availability and potential risks of micro needle fractures. |
Drug delivery. |
Silicon. |
|
4 |
Dissolving Micro needle |
Releases drugs by dissolving under the skin, suitable for macromolecules |
Easy to administer and manufacture, biodegradable |
Manufacturing requires technical expertise, and dissolving takes time. |
Drug and vaccine delivery |
Polymer |
|
5 |
Porous Micro needle |
Drugs are loaded through pores of different sizes during manufacturing. |
Simplest fabrication method and allows higher drug loading |
Limited ability to penetrate the skin effectively. |
Disease diagnosis. |
Stainless steel, Titanium. |
Manufacturing And Present Situation of Microneedles
The Creation and Design of Micro needles When developing MNs for skin penetration, the following important factors should be considered: Hollow, solid, side-opened, bevelled, and conical-tipped properties; material selection; geometric properties including diameter, length, shape, and tip size; array organisation; and production feasibility are all covered in physical (a) and (b) [76]. Drawing lithography, lithography with electroforming, laser drilling, reactive ion etching, hot embossing, injection moulding, and wet chemical etching are among the several fabrication processes used in Minnesota. Currently, the most popular production processes for creating micro needles are silicon deep reactive ion etching (DRIE), micromolding, and photolithography [76,77].The manufacturing of micro needles frequently makes use of microelectromechanical systems. Three processes make up the basic process for creating MNs: (a) deposition, or depositing; (b) patterning, or creating patterns; and (c) etching or engraving [78]. Micro needle devices can be made using a variety of techniques, such as injection moulding, reactive ion etching, isotropic chemical etching, surface/bulk micromachining, and others [78].
Fig No-9: Manufacturing And Present Situation of Micro Needles
Pharmacokinetics, Insertion Behaviour, And Mechanism of MNS Hundreds OF MNS
Medication is applied to the skin using MN arrays, which are individually less than 1 mm long. When an MN array is adhered on an adhesive backing to enhance its skin-adhesion, an MN patch is created [79]. When the medication is injected into the skin's dermis layer, it causes a brief mechanical disruption of the skin, making it easier for it to reach its target location. Additionally, by bypassing still-functioning blood arteries and nerve terminals in the dermis and epidermis, MNs offer micro scale drug delivery pathways. This makes it easier to provide higher dosages and medications with larger molecular sizes and improves the efficacy of drug delivery [80]. For example, biodegradable polymers in a polymer matrix have been used to construct polymeric MN-containing drugs. When these When MNs puncture the skin, the polymers degrade, releasing the medications into the bloodstream and starting a healing reaction [79]. To be reviewed by peers, Pharmaceutics 2023, 15, x 14 out of 28 4.3. MNs' utilisation of pharmacokinetics, insertion, and mechanisms to administer medicine to the skin, hundreds of MNs, each less than 1 mm long, are stacked in an MN array. When an MN array is adhered on an adhesive backing to enhance its skin-adhesion, an MN patch is created [79]. When the medication is injected into the skin's dermis layer, it causes a brief mechanical disruption of the skin, making it easier for it to reach its target location. Additionally, by bypassing still-functioning blood arteries and nerve terminals in the dermis and epidermis, MNs offer microscale drug delivery pathways. This boosts the effectiveness of drug delivery and permits the administration of higher dosages of drugs [80] with bigger molecular sizes. For instance, polymeric medications containing MN have been created using biodegradable polymers in a polymer matrix. The drugs are released into the bloodstream when the polymers in these MNs break down, producing a therapeutic impact at the site of action [81].
Fig No-10: MNs' Mechanism of action
MN-Mediated Antihypertensive Drugs And A Few Said Delivery Systems Based on Nanoparticles
The scientific literature has long proven the connection between high blood pressure and cardiovascular disease. If untreated, hypertension can result in coronary artery disease and renal failure. Despite recent advances in research and treatment, hypertension remains a potentially fatal medical condition [82]. Therefore, in order to improve patients' long-term clinical treatment and outcomes, it is essential to develop and test novel hypertensive medications. Recently, a number of animal models of hypertension have been created to enable in vivo testing of therapeutic approaches and drug effectiveness [83]. Antihypertensive medications can now be gently delivered via the skin barrier using MNs, an alternative drug delivery method. Drug delivery based in Minnesota lowers the possibility of side effects from oral antihypertensive drugs. MNs can also be used to administer antihypertensive medications in sustained-release formulations, which can lower the frequency of doses and increase patient compliance. All things considered, antihypertensive medication distribution headquartered in Minnesota may prove to be a secure and successful therapeutic solution for hypertensive patients. A lot of Studies have been conducted recently create & improve delivery to mechanism of various a antihypertensive medications [84,85]. This article discusses some studies that use Minnesota-based drug delivery for antihypertensive medications. Concurrent medications, such as sodium nitroprusside (SNP) and sodium thiosulphate (ST), were used to create an antihypertensive dissolving MN. SNPs and ST were used in centrifugal casting to create soluble MNs. Using this method, SNPs were quickly introduced into the systemic circulation after being securely packed into micro needles. Blood pressure was rapidly and considerably lowered by antihypertensive micro needle therapy (aH-MN). It complied with clinical guidelines for treating hypertensive emergency blood pressure. The adverse effects (such as organ damage) brought on by SNP consumption were successfully reduced by concurrent delivery of ST. An efficient and biodegradable patch that is easy to use for the controlled administration of medications in antihypertensive therapy was demonstrated in this study [86,87]. To investigate skin penetration, Ahad et al. created a transfer some gel filled with eprosartanmesylate. When compared to an oral formulation, the pharmacodynamics investigation demonstrated improved treatment of hypertension following the application of transfer some gel. Rats' skin was treated with an MN roller, such as a derma roller, to improve the drug's penetration. When an MN was applied beforehand, the transdermal flow of eprosartanmesylate increased by transferosome gel across rat skin [88]
MNS For the Transdermal Administration of Medicines For Hypertension:
Important Features and Future Difficulties to treat hypertension, a number of medications are available in traditional dose forms; however, the majority of antihypertensive medications have inadequate bioavailability due to their poor water solubility. These medications have issues such a high dose frequency, limited intestinal permeability, and a brief half-life. They are Pgp (P-glycoprotein) substrates [89]. MN-based drug delivery works best for antihypertensive medications with low absorption rates. MNs increase percutaneous absorption as the medication enters the systemic circulation directly, Addressing issues related to oral administration of antihypertensive drugs. MNs only damage the stratum corneum and epidermis, causing pores in the skin that are micron-sized; they do not penetrate the dermis to reach blood vessels or nerve fibres. These MNs can provide medications for hypertension. Trans dermally, possibly offering less adverse effects and a more successful course of treatment than conventional oral drugs [90]. Crucial characteristics of MNs for the transdermal administration of hypertension medications are the needles' composition, quantity per patch, diameter and length, and loading of drugs technique. Needles have to be sufficiently long time to pierce the corneum stratum of the skin without causing discomfort by reaching the nerve fibres. The needles should have a diameter that is both sufficiently large to enable effective drug delivery and sufficiently small to minimise discomfort. Given the required drug dosage and delivery rate, the number of needles per patch should be carefully considered. The material of the needles must be strong enough to withstand skin insertion and biocompatible [91]. Ensuring uniform drug distribution across different skin types and circumstances is one of the impending issues related to this strategy. Drug delivery and needle penetration can be affected by several parameters, including skin thickness & degree of moisture. Optimising the drug composition and loading technique for each individual treatment to guarantee the best possible delivery stability and efficiency is another difficulty. Similarly, since the MNs can be utilised at relatively low dosages, difficulties with dose distribution are also evident. Moreover, skin irritation and swelling may result from repeatedly applying MNs at the same spot [92].
Important Features and Future Challenges of Mns for Transdermal Delivery of Hypertensive Medication
To treat hypertension, a number of medications are available in traditional dose forms; however, the majority of antihypertensive medications have inadequate bioavailability due to their poor water solubility. These medications are substrates of Pgp (P-glycoprotein) and possess drawbacks like a high dose frequency, insufficient intestinal permeability, a brief half-life (93). MN-based drug delivery works best for antihypertensive medications with low absorption rates. MNs increase percutaneous absorption as the medication enters the systemic circulation directly, addressing the issues related to antihypertensive drug administration orally. MNs do not pierce the dermis to reach blood vessels or nerve fibres; instead, they only harm the stratum corneum and epidermis, creating micron-sized pores in the skin. Compared to conventional oral pharmaceuticals, these MNs have the ability to trans dermally administer hypertensive medications, which may result in a more effective course of treatment with fewer adverse effects [94].Crucial characteristics of MNs for the transdermal administration of hypertension medications are the needles' composition, quantity per patch, diameter and length, and loading of drugs technique. Needles longer enough reach the nerve fibres in the corneum stratum of the skin without producing pain. The needles should have a diameter that is both small enough to reduce discomfort and large enough to allow for efficient drug delivery. The number number of needles in each patch should be carefully assessed for the planned drug dosage and delivery rate. The needles should be made of a material that is both biocompatible and robust enough to endure being inserted into the skin [95]. Ensuring uniform drug distribution across different skin types and circumstances is one of the impending issues related to this strategy. Drug delivery and needle penetration can be impacted by a number of parameters, including skin thickness and degree of moisture. 96 Optimising the drug composition and loading technique for each individual treatment to guarantee the best possible delivery stability and efficiency is another difficulty. Similarly, since the MNs can be utilised at relatively low dosages, difficulties with dose distribution are also evident.[ 97]
CONCLUSION
MNs are regarded as cutting-edge medication delivery methods with special advantages. Because they distribute active chemicals to the body more safely, effectively, and with superior pharmacokinetics. Desired location, they are the ideal platform for biological and pharmaceutical applications. They have provided innovative ways to use MNs to deliver active medicinal components in diseases that pose a hazard to life. Significant progress has been made in every application area, including immunological-biological, dermatological, disease therapy, disease detection, and cosmetic applications. To get a pharmaceutical release profile, it is essential to select the right material, manufacturing process, needle geometry, and design. Clinical experiments on MNs have been carried out, indicating the scientific community's strong interest in employing devices for a range of medicinal applications. 2023, 15, 2029, 21 of 27; Pharmaceutics. As a result, some MN devices are now available for purchase. Many therapeutic alternatives for oral, buccal, and ocular medication delivery would become available with the development of these minimally invasive instruments. According to certain studies, MN-based delivery improves the transdermal administration of antihypertensive drugs. Further research is required to evaluate MN's effectiveness in treating hypertension. They can be successfully adapted for clinical application once the challenges and restrictions of MN-based antihypertensive drug delivery are better understood. Ultimately, Minnesota-based medication delivery has the potential to revolutionise the treatment of hypertension and improve patient outcomes. The current review study clarifies the difficulties associated with oral drug administration of antihypertensive medications, MN-based delivery of antihypertensive pharmaceuticals, and their effect on hypertension.
REFERENCES
Dr. Karande. Monika Bhosale*, Dr. V. Y. Lokhande, Microneedle for the Transdermal Delivery of Hypertensive Drugs, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 1732-1758 https://doi.org/10.5281/zenodo.15211904
10.5281/zenodo.15211904
