Overcoming Skin Barrier Limitations in
Antihypertensive Therapy: Emerging Innovations in Transdermal Patch Design
Syed Imran1*, Dr. Prafulla Prakash Adkar Patil2
1 Research Scholar, Sunrise University,
Alwar, Rajasthan, India
syedimran665@
2 Professor, Department of Pharmaceutical Sciences, Sunrise University, Alwar, Rajasthan, India
Abstract: Hypertension continues to be a major global health issue that requires lifelong pharmacological therapy. Nevertheless, conventional oral antihypertensives have some limitations, including first-pass metabolism, variable plasma drug concentrations, and noncompliance. Compared to these types of products, transdermal drug delivery systems offer specific advantages , including the ability to control the release of a drug, obtain consistent levels of drug therapy, and improve patient compliance. Unfortunately, transdermal drug delivery is compromised by the barrier characteristics of the stratum corneum, which results in the need for innovative methods to increase the permeability of the skin.
This review utilized a meta-analysis with published peer-reviewed articles, scientific literature, and pharmaceutical databases that reported recent advances in transdermal antihypertensive therapies. Four primary areas of focus include chemical and physical methods to enhance permeation, delivery systems using nanocarriers, lipid-based formulations, and polymer-based engineering used in the design of transdermal patches. The four methods were analyzed for their mechanisms of action, their effectiveness, and ability to overcome stratum corneum barrier properties.
Chemical enhancers or physical methods of enhancing absorption disrupt the skin barrier for only a limited time, while use of a nano-carrier system and lipid systems will improve drug solubility/pentration/release and provide a much longer-lasting means than previous systems. Modifications to polymers used for the formulation of pharmaceutical will have an additional factor to help control the delivery of drugs as well as to improve the overall stability of the drug delivery system. When using the principles of diffusion to help guide the development of formulations, overall efficiency and predictability can be maximized.
It was concluded that there are remaining gaps in terms of safety, stability and scalability of the development of transdermal methods of administering antihypertensive medications. Significant advances in technology will continue to provide opportunities for advances in transdermal medication delivery and the ultimate treatment of high blood pressure. Continued advances in technology used for transdermal medication delivery can only be achieved with a multidisciplinary approach of combining innovative materials and drug transport principles to develop future products.
Keywords: Transdermal drug delivery, Antihypertensive therapy, Skin permeability, Nano-carriers, Polymer engineering
Hypertension, or high blood pressure, is a condition defined by above average arterial blood pressure. Systolic blood pressure is measured above 140 mmHg and diastolic pressure is measured above 90mmHg. Hypertension is one of the leading risk factors for cardiovascular disease; for example, it is one of the leading causes of stroke, heart attack (myocardial infarction), and heart failure. According to research done by the World Health Organization, there are more than 1 billion people that have hypertension around the world and that contributes significantly to early death and disability, especially in low and medium-income countries where the awareness and adherence to treatment for hypertension is poor (Mills et al, 2020). The rise in the number of people suffering from hypertension, due in large part to poor diet, sedentary lifestyle, an increase in the age of most people, and urbanization has increased the need for long term, affordable and sustainable treatment options.
In treating hypertension, most patients take oral medications such as beta blockers or ACE inhibitors for high blood pressure; however since these types of medications are commonly used, they have numerous disadvantages which affect how well they work. One of the most prominent issues is first-pass metabolic activity in the liver, which can drastically lower the bioavailability of nearly all medications before they enter the bloodstream. Additionally, many oral medications display substantial variability in gastrointestinal absorption due to various factors such as pH levels, food interactions, and the presence of digestive enzymes (Sharma et al., 2019). As a result of these issues, fluctuations of the plasma concentration of medication can cause less consistent therapeutic outcomes than expected.
In addition to the above-mentioned limitations associated with oral antihypertensive treatment; patient non-adherence with their prescribed treatment regimen is very problematic. The extended duration between refills, numerous doses per day, and side effect issues associated with long-term therapy discourages many patients from following their prescribed regimen. The patient who does not closely adhere to his/her prescribed medication regimen will present with poorly controlled blood pressure while also increasing the risk of future health problems. Given this scenario, alternative drug delivery systems that can produce prolonged-release effects, lower required dosing frequencies, and provide greater patient convenience have become increasingly attractive.
TDDS (transdermal drug delivery systems) have emerged as the most promising alternative to conventional oral administration. TDDS allow for the delivery of drugs directly through the skin into the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism by the liver. Some benefits of TDDS include controlled release of medication, stability of plasma levels of medication, increased bioavailability, and improved patient compliance. Additionally, transdermal patches are non-invasive, convenient to use, and may be configured for prolonged delivery of medication; thus, they are ideal for chronic illnesses (such as hypertension) (Kumar et al., 2018). As promising as TDDS may be, their success is limited primarily by the barrier characteristics of the skin. Most importantly, the stratum corneum (the outermost layer of the epidermis) offers the greatest resistance to drug permeation through the skin.
The skin is an extremely complicated organ that plays many different roles including being the main barrier between the body and the outside world. The skin consists of three layers (epidermis, dermis, hypodermis). The outermost layer of the skin is the epidermis and contains the stratum corneum which is the primary barrier against drug penetration through the skin. The outer layer of skin is known as the stratum corneum and is made up of keratin-rich dead cells that are arranged in a lipid-protein order. It has often been compared to brick-and-mortar buildings, in which there are "bricks" that are the keratinocytes and "mortar" that is the intercelilly lipids that hold the "bricks" together.
This organized structure allows for an effective barrier to prevent anything from entering the body while still allowing for the loss of water. However, this same barrier also makes it difficult for drugs to be absorbed through the skin because of the tight packing of the lipid bilayer and low levels of hydration in the stratum corneum. Thus, few drugs can penetrate through this barrier due to the physicochemical properties of the drug. Specifically, only drugs with low molecular weights and moderate lipophilicities can cross through the barrier (Prausnitz et al., 2004).
There are three routes that drugs can take to move through skin: Intercellular (between lipid layers), Transcellular (through corneocytes) and Appendageal (protozoan through hair follicles or sweat glands). The intercellular route is generally thought to be the most important method of drug delivery for most drugs. The resistance produced by the stratum corneum can be affected by various variables including lipid content, thickness, hydration levels, and the environment.
It is vital to successfully overcome this barrier in order to develop a transdermal antihypertensive treatment. While transdermal drug delivery systems represent a potential therapeutic advantage in treating hypertension, they face multiple limitations in their current application in antihypertensive treatments. One such limitation is the poor permeability of many antihypertensive medications through the skin due to their physicochemical properties like large molecular size or high polarity preventing easy diffusion across the stratum corneum leading to difficulty achieving therapeutic concentrations in systemic circulation.
Conventional transdermal patches also face problems associated with the pharmaceutical formulation used in them. For instance, drug formulation issues lead to suboptimal performance of the transdermal patch system due to insufficient capacity for drug loading, inconsistent release rates, and skin irritation resulting from the chemical properties of the formulation used. These problems adversely affect the clinical effectiveness and acceptance of the transdermal delivery system. In addition, the absence of consistent methods to develop and optimize drug permeation, stability, etc., make developing transdermal systems more difficult.
As such, there is an urgent need for innovative methods to improve skin permeability whilst ensuring safety and efficacy. Recent advancements in pharmaceutical technology (i.e. permeation enhancers, nano-carriers, lipid-based systems, polymeric modifications, etc.) have provided an excellent means to address the aforementioned problems.
Due to an increasing demand for non-invasive and patient-friendly drug delivery systems, there has been a marked increase in the research of transdermal therapeutic systems. This increased interest in transdermal delivery systems is highly significant in managing hypertension, which requires long-term use of medications, as improving both drug delivery efficiency and, thus, patient compliance, is critical. Therefore, transdermal systems may address these challenges by providing controlled/sustained delivery rates, reducing dosage frequency, and also decreasing the side effects related to the medications used to treat these chronic disease conditions.
Another impetus of this study is to improve the bioavailability and clinical stability of antihypertensive medications by using transdermal (TD) delivery systems to avoid gastrointestinal (GI) and first-pass hepatic metabolism; this would allow for more reliable pharmacokinetic (PK) properties and better patient outcomes. In addition, advances in formulation science and materials engineering have provided substantial opportunities for optimizing TD drug-delivery systems.
From an industrial viewpoint, the creation of new TD patches offers a significant opportunity for pharmaceutical industry innovations and expanding market share. Chronic diseases are becoming more frequent, and increased interest in the personalization of healthcare necessitate an effective, flexible platform with the capacity to deliver medications safely and effectively. Consequently, a comprehensive review of technology advancements in regard to transdermal hypertension treatments is timely and pertinent.
The purpose of this study was to identify new ideas that can help to solve problems faced by drugs trying to cross barriers caused by the skin when delivering antihypertensive medications through the transdermal route. This study will be looking specifically at how to utilize what is known about how to deliver drugs into the body (principles of drug transport) and how to use advances in formulation technology to find new ways of overcoming these difficulties. Specifically, the study will be investigating how permeation enhancers may improve drug delivery by increasing the speed at which drugs diffuse through the stratum corneum, how the use of nano-carrier or lipid-based delivery systems would increase the bioavailability of an antihypertensive drug, and how to change the polymeric components within the design of a transdermal patch in order to achieve a specific, controlled, and sustained rate of delivery.
The study was conducted using an analytical review based upon previously published secondary data. Data and information related to this research were obtained from reputable and readily available sources, such as: Pub Med, Google Scholar, World Health Organization reports, and related databases from pharmaceutical research. Research articles were selected from the available literature according to pre-defined inclusion criteria. Studies included in this analysis were those that were pertinent to the transdermal delivery of antihypertensive agents and additional methods to enhance the permeability of the skin.
Identifying
key trends, innovations and research gaps within the field, peer-reviewed
articles, review papers and scientific reports published from 2000 - 2024 were
systematically reviewed for identifying those trends and innovations. Using
thematic analysis, the findings were grouped into large thematic categories;
permeation enhancement methods, nano-carrier methods, lipid-based formulations,
and polymer modifications. All collected data were critically analyzed to
determine the effectiveness, safety and practicality of each method in
addressing the limitations of skin barrier. This methodology provided a
comprehensive and systematic synthesis of existing knowledge and enabled
development of valuable insights and recommendations for future research and
clinical applications.
The
effectiveness of transdermal drug delivery systems in delivering
antihypertensive drugs can be greatly improved through various permeation
enhancement strategies, which help to overcome the resistance of the stratum
corneum. These strategies can be used to cause temporary changes in the
structure of the skin barrier, or assist in transporting the drug across the
barrier, without causing any permanent injury. Generally, these strategies are
classified as either chemical or physical methods, each of which has its own
mechanism for enhancing drug penetration.
Chemical
permeation enhancers are among the most widely used and researched
methodologies to aid in the transdermal delivery of drugs. Chemical enhanced
drug deliveries through the skin are a result of multiple interactions
occurring between the lipid and protein components of the stratum corneum which
increase the permeability of the skin. There are several chemical enhancers
which can be classified into common classes, alcohols, fatty acids and
surfactants.
Ethanol
is one of the most commonly used chemical enhancers for drug delivery systems
because of its ability to solubilize drug compounds and disrupt lipid
organization in the stratum corneum. By extracting the lipids, ethanol
increases the flexibility (or fluidity) of the lipid bilayer to promote the
diffusion of drug compounds to penetrate through the skin (Williams &
Barry, 2012). In addition to ethanol, fatty acid such as oleic acid can also
serve as effective permeation enhancers. Fatty acids enhance the permeation of
drug compounds by inserting into the lipid matrix thereby disrupting the lipid
structure and creating micro-channels for improving the diffusion of a drug
compound.
Surfactant
based chemical enhancers utilize different interactions, with both the lipid
and protein components of the skin. Surfactants can solubilize lipids and
denature keratin in the corneocytes reducing the barrier of resistance.
However, the use of surfactants must be controlled in order to prevent
irritation and/or toxicity to the epidermis. In summary, chemical permeation
enhancers provide an easy and economical method to enhance transdermal drug
delivery systems, however, the safety profile of chemical permeation enhancers
is a major concern.
In addition to using chemicals as a method of enhancing skin penetration, there are a wide variety of physical enhancement methods that have been developed as a means of improving skin penetration without the use of chemicals. These methods utilize external physical forces or devices to aid in transporting drugs from the outside environment through the skin and into the body.
Among the many physical enhancement methods, microneedles may be one of the most promising methods of enhancing skin penetration. Microneedles are very small needles that form temporary micropores in the skin; therefore, the drug can bypass the stratum corneum and penetrate into deeper layers of the skin. Because of their small size, microneedles are minimally invasive and cause little or no pain when used; therefore, microneedles may prove to be patient friendly. Microneedles have been demonstrated to greatly improve the delivery of both small molecules and macromolecules through the skin.
Similarly, iontophoresis is a physical enhancement technique that uses a low-level electrical current to drive the delivery of positively or negatively charged drug molecules through the stratum corneum and into the body. Iontophoresis increases the transport of drugs through the stratum corneum by enhancing the mobility of ions within the skin layer and altering the electrical properties of the skin. Likewise, sonophoresis utilizes ultrasound waves to disrupt lipid structures in the stratum corneum and increase the permeability of the stratum corneum to allow drugs to permeate through the stratum corneum. All of these physical enhancement methods produce temporary and reversible disruptions of the skin barrier to enhance the diffusion of drugs, without causing irreversible changes to the skin barrier (Kim et al., 2012).
Transdermal
permeation enhancement strategies can be extremely beneficial; however, it is
essential to evaluate the permeability enhancer strategies benefits against any
associated safety issues. In particular, skin irritation is one of the most
common concerns from both the use of chemical / physical enhancers to enhance
permeability. Chemical permeation enhancers (i.e., surfactants, high
concentrations of alcohol) can lead to erythema, dryness and discomfort.
Physical techniques for topical drug delivery (i.e., microneedles,
iontophoresis) may cause mild skin reactions when both do not have proper
control mechanisms.
Another
important safety issue regarding the use of permeation enhancers is whether the
disruption of the skin barrier is reversible. The primary goal of permeation
enhancers is to induce a temporary alteration of the skin's normal structure
and function, which should return to normal shortly after treatment. This
allows time for the skin's protective barrier to regenerate and minimizes the
risk of skin infections and long-term skin damage. It has been shown that many
physical techniques including microneedles and ultrasound, produce reversible
results and therefore pose a relatively low risk of injury due to continual use
(Donnelly et al., 2010).
In
addition to safety issues, clinical feasibility is an important consideration
in the development of transdermal delivery systems. Factors such as usability,
comfort of the subject/patient, cost-effectiveness, and scalability must also
be taken into account when determining the clinical applicability of any
particular technology. Although most sophisticated technology delivers a
superior product, when incorporating such technology into the practice of
medicine, one must pay as much attention to the optimization of efficacy,
safety, and convenience for the user as one does to the sophistication of the
technology being incorporated into clinical practice.
The emergence of nano-carrier systems as a novel approach to transdermal drug delivery is changing how we administer antihypertensive medications, because skin can be a barrier to these medications. The use of nanoscale carriers (nanocarriers) to encapsulate drug molecules improves the solubility, stability, and controlled release of these drugs, thereby increasing the efficiency of transdermal absorption as well as the therapeutic effectiveness of transdermal drug administration. Nanocarriers also enhance the interaction between drug molecules and the skin, which increases the effectiveness of the drug on the skin (Patel et al., 2012).
Several types of nano-carriers have been developed for transdermal applications, each with Liposomes are vesicles created of a lipid bilayer, used to get both hydrophilic and hydrophobic drugs into cells. Because of their biocompatibility and "compatibility" with skin lipids, they are particularly well suited to enhance drug penetration. Niosomes have the advantage of greater stability than liposomes because they are constructed of non-ionic hydrophilic surfactants, making them less prone to oxidization. Additionally, niosomes provide an economical alternative to liposomes and also have a high capacity for drug encapsulation. Solid lipid nanoparticles are another type of nano-carrier composed of solid lipid matrices that maintain stability under normal body temperature and provide controlled release of encapsulated drugs protecting them from degradation.
Nanostructured lipid carriers, which are based on solid lipid nanoparticles but also contain liquid lipids, have an increased capacity for drug loading, due to their more disorganized and less ordered lipid structures, as well as more favourable release profiles than solid lipid nanoparticles. These nanostructured lipid carriers have also exhibited superior permeatin opportunities and higher drug stability (Müller et al., 2011).
Nano-carriers assist in getting drugs through the skin using several different ways. A key way is that there is a greater surface area with nanoscale particles, which means they can do more interacting with the skin surface than larger particles can. How much better drugs permeate through the skin is determined by having more surface area contact with the skin surface.
Also, the nano-carrier affects the lipid components of the stratum corneum by disrupting the lipid structures that are tightly packed together and increasing the fluidity of those structures. This allows for easier diffusion of drug molecules across the skin barrier. Another way in which nano-carriers could assist penetration is through follicular delivery, which involves the nano-carrier being able to enter the hair follicles (and accompanying sebaceous glands). These appendageal pathways can be used as a means to store drugs that will be released in a controlled and sustained manner (Prow et al., 2011).
Nanocarrier systems have demonstrated significant promise in the transdermal delivery of antihypertensive medications including clonidine and propranolol. Clonidine is a centrally-acting antihypertensive that has been successfully developed using liposomes and solid lipid nanoparticles as transdermal drug delivery systems to provide improved bioavailability and prolonged pharmacological effects. Propranolol has the additional complication of very high first-pass metabolism when delivered orally; therefore, propranolol has the potential to have reduced variation in plasma concentrations via a transdermal route utilizing nano-carrier systems.
Both of these nano-carrier systems not only enhance the permeation of the drug through the skin but also provide sustained release profiles allowing for less frequent dosing and increased patient compliance. The ability to achieve stable concentrations of the drug in the bloodstream is of significant benefit for the treatment of chronic diseases such as hypertension, in which stable and consistent therapeutic effects are required (Benson, 2005).
Although
there are many benefits associated with using nano-carrier systems, there are
also several limitations that prevent these systems from becoming widely
adopted. One major limitation of nano-carrying agents is that they eventually
aggregate and form clumps of nanoparticles together, making them less effective
and unstable. Aggregation will lead to decreased efficiency of drug delivery
and reduced shelf-life of drug products.
The
stability of nano-carrying systems depends greatly on the conditions under
which they are stored. Storage conditions such as temperature, humidity, and
light exposure will drastically affect the stability and integrity of the
lipid-based systems; thus the potential for drug leakage or degradation exists.
Another limitation to the successful manufacturing of nano-carrier systems is
the complexity and cost associated with the fabrication process; due to the
specialized equipment required and the need for strict quality control
protocols.
The
above-mentioned limitations of nano-carrier systems point to the importance of
continued research and development in order to discover a more cost-effective,
stable, and scalable means by which to produce and supply nano-carrying systems
for use in transdermal antihypertensive therapy. In order to successfully
translate laboratory innovation into real-life clinical use, it will be
necessary to resolve these limitations and barriers.
Considerable
progress in the development and use of transdermal patchesystems, especially
those intended for the treatment of hypertension, through use of both polymer
engineering and lipid-based systems. These approaches strive to enhance drug
permeation through the skin while providing controlled release, stability and
acceptance. The use of lipid vesicular carriers and optimal polymer matrix
systems can be utilised in combination to create a new generation of
transdermal systems that are capable of addressing the deficiencies of
traditional patch technology.
Lipids are becoming increasingly popular as carriers because they can merge with the lipids found naturally in our skin, therefore helping with the delivery of drugs through the skin and into the bloodstream. Ethosomes are the most commonly researched type of lipid based carrier. Ethosomes contain lots of ethanol, and the addition of ethanol makes the lipid bilayers in the stratum corneum more fluid so that the drug molecules can penetrate deeper into the skin. Ethosomes increase the solubility of drugs and are able to deliver both polar (water-soluble) and non-polar (lipid-soluble) drugs (Touitou et al., 2000).
Transfersomes are a significant group of lipid vescicles characterized by their exceptional deformability. These flexible vesicles are capable of passing through narrow spaces between skin cells, facilitating the delivery of drugs across the stratum corneum. The high elasticity of transfersomes is attributed to the addition of edge activators (e.g., surfactants) that destabilize the lipid bilayer and provide an increased level of elasticity.
Microemulsions are thermodynamically stable mixtures of oil, water, surfactants, and cosurfactants that provide an extensive interfacial area for drug solubilization and enhance drug transport through the skin. Microemulsions have been demonstrated to be stable and easy to prepare, making them an attractive option for use in transdermal dosage forms and providing enhanced drug delivery performance (Lawrence & Rees, 2012).
Transdermal patches use polymers as their primary structural component, which provides the backbone for how the drug will be released and the mechanical properties of the patch. The type of polymer used will have a large effect on how the patch performs, including adhesion to the skin, flexibility and the rate at which drugs diffuse out of the patch into the bloodstream.
Hydrophilic polymers such as polyvinyl alcohol and hydroxypropyl methylcellulose release drugs quickly because they have a strong affinity for water. Hydrophobic polymers such as ethyl cellulose release drugs over an extended period because they slow down the rate at which drugs can diffuse out of the polymer matrix.
The rate at which drugs are released from transdermal patches with controlled release systems can be controlled by manipulating the design of the polymer matrix to control the rate of drug diffusion through the matrix. This can be accomplished through various means, including cross-linking of polymers, blending of different types of polymers, and using plasticizers. These changes will help to ensure that the patches provide a consistent and effective drug release profile over time, which is necessary for successful treatment of high blood pressure (Siepmann & Siepmann, 2012).
Recent breakthroughs in the field of polymer technology have resulted in new responsive/smart polymers capable of responding to various environmental stimuli, such as changes in pH, temperature or ionic strength. These types of polymers are beneficial in enabling on-demand or controlled therapeutic delivery, as well as providing more precise delivery of therapeutic agents with fewer adverse effects. One example is temperature-sensitive polymers, which adjust their physical structure according to body temperature (skin temperature), therefore modulating the rate at which a drug will be released from a polymer matrix/post-drug delivery system.
An additional innovative type of polymer used for transdermal delivery of a therapeutic agent is called bioadhesion polymer; this type of polymer increases the degree of adhesion between the patch and the underlying skin tissue (i.e., bioadhesive polymer) to allow for prolonged contact and increased absorption of a drug contained within the patch. Bioadhesive polymers improve the clinical efficacy of the delivery system through various types of chemical interactions that occur between the patch and skin (e.g., hydrogen bonds or electrostatic interactions). This results in a greater residence time of the patch on the skin, thereby increasing the efficiency of drug delivery (Peppas et al., 2006).
The design / optimization of transdermal systems relates directly to the diffusion models used to describe drug molecule movement across a concentration gradient (specifically, Fick's law). Drug permeation rate is determined by several factors including: (1) the drug concentration difference between the two sides of the barrier, (2) the diffusion coefficient of the drug, and (3) the thickness of the barrier.
The use of mathematical modeling for drug release kinetics in system forms utilizing polymers can help predict and control release rates through combination with diffusion models in order to identify optimum system parameters, such as drug flux and permeability. By utilizing this type of science to complement the development of pharmaceutical formulation, researchers can improve the predictability and reliability of transdermal antihypertensive systems (Hadgraft, 2004).
Transdermal drug delivery systems, which use innovative and advanced lipid-based or polymer-engineered technology, have tremendous commercial and industrial opportunities. Important factors in scalability include optimizing the process for large-scale production whilst maintaining quality and consistency. Solutions such as hot-melt extrusion and solvent casting are standard processes used for large-volume production.
The regulatory authorities require comprehensive evaluation of the transdermal patch on safety, efficacy, and stability before they approve for commercialisation. This includes conducting clinical trials, performing quality control testing, and meeting the specified standards for compliance with international guidelines.
The market also has a growing demand for transdermal drug delivery systems, which are non-invasive, convenient and have improved therapeutic outcomes. The growing use of innovative lipid carriers and smart polymers will help lead to further growth in this market and specifically in diseases that are chronic in nature, such as hypertension. Therefore, further development and research in this area are needed to develop science into solutions for healthcare solutions that can be used commercially.
This research aimed to assess the use of transdermal systems for delivering antihypertensive medicines as an alternative to traditional oral systems and their advantages. The results of the study showed that using transdermal systems to deliver antihypertensive drugs has a number of significant advantages over using traditional oral delivery such as avoiding first-pass metabolism; increasing bioavailability; providing a sustained dose of medication and promoting patient compliance with medications. These characteristics support the idea that transdermal systems can provide an effective long-term solution for managing hypertension, a chronic disease requiring ongoing consistent medication.
The
findings also pointed out that there are limitations to the ability of
transdermal systems to deliver antihypertensive drug molecules through the
skin. Of the several skin layers, the stratum corneum was identified as the
greatest barrier to effective antihypertensive drug delivery. The tightly
structured lipid-protein matrix that make up the stratum corneum was found to
severely restrict the ability of most drug molecules, particularly those which
had less suitable physicochemical properties to penetrate the stratum corneum.
This has greatly limited the number of drugs that can be successfully delivered
via transdermal patch therapy.
A
variety of approaches were explored to solve this issue. The study found that
chemical permeation enhancers, such as alcohols, fatty acids and surfactants,
were beneficial for temporarily disrupting the skin barrier and allowing drugs
to diffuse through. Additionally, physical methods such as microneedles and
iontophoresis were shown to create controlled and reversible pathways for
transporting drugs, which increased permeability without causing permanent
harm.
The
study also revealed large increases in drug solubility, stability, and
controlled release from nano-carrier based systems, including liposomes,
niosomes, solid lipid nanoparticles, and nanostructured lipid carriers.
Nano-carrier systems created increased drug penetration through increased
surface contact, disruption of lipids, and filling of follicles with delivery
pathways. Also, lipid carriers, such as ethosomes and transfersomes, were found
to have superior ability to interact with skin lipids and promote deeper drug
penetration.
Mono-directional
drug delivery devices can be made much more efficient by covering them with a
polymer film that uses both hydrophilic and hydrophobic polymers. The 3D
organization created by these polymers allows precise control of drug release
and provides a route for new types of polymer films to be utilized for drug
delivery, e.g. smart and responsive systems. Finally, an important enhancement
to the prediction and efficiency of drug delivery is the integration of
diffusion theory (principally Fick's law) into the design of formulations.
In
conclusion, the incorporation of increased knowledge regarding the mechanisms
through which drugs are transported combined with advanced formulation
techniques has turned previously unattainable goals into reality by making
transdermal antihypertensive therapy much more likely. Findings from this study
provide strong evidence that the future of transdermal delivery systems, as
effective and patient-friendly therapeutic alternatives, is brighter than ever
before.
The results of this research provide the following recommendations for further developing and applying transdermal antihypertensive delivery systems: First, there is a need for safer, more biocompatible permeation enhancers. Currently, chemically based permeation enhancers have been proven effective; however, due to the potential for causing irritation and toxicity to skin tissues, more biocompatible alternatives need to be studied.
Second, clinical trials must be carried out over long periods of time in order to evaluate the continued safety, efficacy, and stability of nano-based delivery methods. While laboratory research has shown promise, data obtained through well-designed clinical trials are necessary to provide a basis for reliability and acceptance of nano-based delivery systems during regular medical practice.
In addition, there should be greater emphasis placed on developing biodegradable, patient-friendly materials in producing transdermal antihypertensive products. By selecting more environmentally friendly and non-toxic materials for patch production, patient comfort is improved and concerns about environmental impact and medical waste are eased.
In addition, federal regulatory agencies should provide some level of standardization when developing and authorizing management of advanced transdermal systems. Establishing standard guidelines for regulatory approval, as well as creating harmonized regulatory procedures, would improve the likelihood that the innovative technologies emerging from research will be transitioned into commercially viable products, and will ensure quality and safe performance in consistent manners. Still, without clear rules, even strong innovations remain confined to the lab. Future studies probably should look at hybrid delivery systems, blending nano-carriers with physical methods or smart polymers together. Such combinations may work better at tackling current challenges and deliver stronger options for antihypertensive treatment.
Scaling-up
and safety now drive transdermal drug delivery systems. Development spans
multiple disciplines. It seems these factors will unlock the full clinical and
commercial promise of the technology.
1. Benson, H. A. E. (2005). Transdermal drug delivery: Penetration enhancement techniques. Current Drug Delivery, 2(1), 23–33.
2. Burnier, M. (2006). Drug adherence in hypertension. Pharmacological Research, 54(6), 393–396.
3. Donnelly, R. F., Singh, T. R. R., & Woolfson, A. D. (2010). Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety. Drug Delivery, 17(4), 187–207.
4. Hadgraft, J. (2004). Skin, the final frontier. International Journal of Pharmaceutics, 276(1–2), 1–18.
5. Kim, Y. C., Park, J. H., & Prausnitz, M. R. (2012). Microneedles for drug and vaccine delivery. Advanced Drug Delivery Reviews, 64(14), 1547–1568.
6. Kumar, P., Singh, S., & Kumar, R. (2018). Transdermal drug delivery system: A review. International Journal of Pharmaceutical Sciences and Research, 9(6), 2199–2210.
7. Lawrence, M. J., & Rees, G. D. (2012). Microemulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews, 64(Suppl), 175–193.
8. Mills, K. T., Stefanescu, A., & He, J. (2020). The global epidemiology of hypertension. Nature Reviews Nephrology, 16(4), 223–237.
9. Müller, R. H., Radtke, M., & Wissing, S. A. (2011). Nanostructured lipid matrices for improved microencapsulation of drugs. International Journal of Pharmaceutics, 242(1–2), 121–128.
10. Patel, A., Singh, S., & Singh, R. (2012). Nanosuspension: An approach to enhance solubility of drugs. Journal of Advanced Pharmaceutical Technology & Research, 3(2), 81–87.
11. Peppas, N. A., Bures, P., Leobandung, W., & Ichikawa, H. (2006). Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics, 50(1), 27–46.
12. Prausnitz, M. R., Mitragotri, S., & Langer, R. (2004). Current status and future potential of transdermal drug delivery. Nature Reviews Drug Discovery, 3(2), 115–124.
13. Prow, T. W., Grice, J. E., Lin, L. L., Faye, R., Butler, M., Becker, W., Wurm, E. M. T., Yoong, C., Robertson, T. A., Soyer, H. P., & Roberts, M. S. (2011). Nanoparticles and microparticles for skin drug delivery. Advanced Drug Delivery Reviews, 63(6), 470–491.
14. Sharma, G., Dhawan, S., & Nanda, S. (2019). Oral drug delivery: Challenges and advancements. Journal of Drug Delivery Science and Technology, 53, 101213.
15. Siepmann, J., & Siepmann, F. (2012). Modeling of diffusion controlled drug delivery. Journal of Controlled Release, 161(2), 351–362.
16. Touitou, E., Dayan, N., Bergelson, L., Godin, B., & Eliaz, M. (2000). Ethosomes—novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. Journal of Controlled Release, 65(3), 403–418.
17. Verma, D. D., & Fahr, A. (2004). Synergistic penetration enhancement effect of ethanol and phospholipids on the topical delivery of cyclosporin A. Journal of Controlled Release, 97(1), 55–66.
18. Williams, A. C., & Barry, B. W. (2012). Penetration enhancers. Advanced Drug Delivery Reviews, 64(2), 128–137.