1 Head of Department, Associate Professor of Pharmaceutics, Bhupal Nobles’ College of Pharmacy, Udaipur, Rajasthan
2 Lecturer, N. S. S. College of Pharmacy, Mumbai, Maharashtra.
Nanocarrier-based transdermal drug delivery systems (TDDS) represent cutting-edge innovations in delivery methods, offering enhanced drug penetration through the skin, which serves as a significant barrier in traditional TDDS. This review aims to offer a comprehensive analysis of nanocarrier-based transdermal drug delivery systems (TDDS), focusing on their mechanisms, types, advantages, challenges, and future prospects. The primary objective is to highlight the key benefits of these systems, including improved drug permeability, controlled and sustained release, targeted delivery, reduced systemic side effects, and enhanced stability. The review encompasses a range of nanocarriers, including liposomes, niosomes, nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), polymeric nanoparticles, dendrimers, and hydrogels, each distinguished by unique properties that enhance their efficacy in transdermal drug delivery systems (TDDS). Key findings underscore the significant potential of these systems in clinical applications such as pain management, hormone replacement therapy, treatment of dermatological disorders, cancer therapy, and vaccination. However, challenges such as skin irritation, complex manufacturing processes, regulatory hurdles, scalability issues, and limited drug loading capacity need to be addressed. Overall, this review underscores the promising future of nanocarrier-based TDDS, with ongoing research focused on smart nanocarriers, personalized medicine, combination therapies, and advanced characterization techniques, paving the way for improved patient outcomes and expanded therapeutic possibilities.
Transdermal drug delivery systems (TDDS) are a sophisticated method of administering medications through the skin, allowing for the direct absorption of drugs into the bloodstream. Unlike oral or injectable routes, TDDS offers a non-invasive and convenient alternative for delivering therapeutic agents. This method utilizes a patch or gel applied to the skin surface, from which the drug diffuses through the epidermis and into the systemic circulation. Transdermal drug delivery systems (TDDS) have garnered considerable attention for their ability to offer controlled and sustained release of medications, thereby improving therapeutic efficacy and enhancing patient compliance1.
Importance and Benefits of TDDS
TDDS present several notable advantages over traditional drug delivery methods:
1. Non-Invasive Administration: TDDS eliminates the need for needles, reducing the risk of infections and improving patient comfort, especially for those with needle phobia.
2. Controlled Release: The ability to provide controlled and sustained drug release minimizes fluctuations in drug concentrations, leading to more consistent therapeutic effects and reduced side effects.
3. Improved Compliance: By simplifying the medication regimen (e.g., a once-daily patch), TDDS enhances patient adherence, particularly for chronic conditions requiring long-term treatment.
4. Bypassing the Gastrointestinal Tract: TDDS avoids the gastrointestinal tract, thereby preventing drug degradation due to stomach acid and enzymes, and eliminating issues related to first-pass metabolism in the liver.
5. Steady Plasma Levels: The continuous delivery of drugs through TDDS maintains stable plasma drug levels, which is particularly beneficial for medications with narrow therapeutic windows2.
Challenges of Traditional TDDS, Particularly the Stratum Corneum Barrier
Despite the advantages, traditional TDDS face significant challenges, primarily due to the outermost layer of the skin, stratum corneum. The stratum corneum acts as a formidable barrier to drug penetration, characterized by its thick, keratinized cells and lipid-rich matrix. This barrier function is crucial for shielding the body from environmental threats and reducing water loss, yet it also restricts the transdermal absorption of numerous drugs.
Key challenges include:
1. Low Permeability: The stratum corneum’s low permeability restricts the types and sizes of molecules that can pass through, making it difficult for large or hydrophilic drugs to penetrate effectively.
2. Variable Skin Conditions: Factors such as skin thickness, hydration, and integrity can vary widely among individuals, affecting the consistency and predictability of drug delivery.
3. Limited Drug Loading: The amount of drug that can be incorporated into a patch or gel is often limited, restricting the total dose that can be delivered transdermally3.
Introduction to Nanocarriers as a Solution
To overcome these challenges, nanocarriers have emerged as a promising solution for enhancing the efficacy of TDDS. Nanocarriers are nano-sized particles designed to encapsulate drugs, improving their stability, solubility, and penetration through the stratum corneum. By leveraging the unique properties of nanotechnology, Nanocarriers can facilitate the transport of a diverse array of therapeutic agents across the skin barrier.
Key advantages of nanocarriers in TDDS include:
1. Enhanced Penetration: Nanocarriers enhance drug permeation by interacting with the skin’s lipid matrix, effectively disrupting the barrier properties of stratum corneum.
2. Targeted and Controlled Delivery: Surface modification of nanocarriers enables targeted delivery to specific skin layers or cells, enabling localized treatment while minimizing systemic exposure.
3. Increased Drug Loading Capacity: Nanocarriers can encapsulate higher concentrations of drugs, enabling the delivery of therapeutically relevant doses through the skin.
4. Protection of Encapsulated Drugs: By protecting drugs from degradation and enhancing their stability, nanocarriers ensure that a higher proportion of the active drug reaches the target site4.
Mechanisms of Transdermal Drug Delivery
Nanocarriers represent promising approach to enhance transdermal drug delivery by overcoming the barriers posed by the skin, particularly the stratum corneum, and improving efficacy and specificity of drug delivery. Mechanisms by which nanocarriers facilitate transdermal drug delivery include:
Fig. 1: Diagram depicting a structure of skin and b routes of drug permeation through its layers 7
Nanocarriers, typically sized between 10 and 1000 nanometers, feature a significant surface area relative to their volume. This characteristic enables close interaction with the skin's surface upon application of the drug formulation. Their small size enhances the interaction with the stratum corneum, facilitating deeper penetration in the skin layers compared to larger drug molecules or conventional formulations.
Nanocarriers wrap drugs inside them, which helps dissolve hydrophobic drugs better or shield delicate drugs from breaking down. This wrapping doesn't just make drugs more stable during storage and when they're given, but it also means more of the drug goes to the right spot in the layers of your skin. By keeping the drug safe until it gets to where it's supposed to go, nanocarriers make drugs work better and more effectively.
The design of nanocarriers allows for controlled release of drugs over an extended period of time. Depending on the formulation and composition of the nanocarrier, drugs can be released through diffusion, degradation of carrier materials, or responsive mechanisms triggered by external stimuli (e.g., temperature, pH, enzymes). This release profile which is controlled, helps maintain therapeutic drug concentrations in the skin or systemic circulation, thereby reducing the frequency of dosing and minimizing fluctuations in drug levels. It also enhances patient compliance and improves therapeutic outcomes by providing a consistent supply of the drug over time.
When nanocarriers are modified on their surface with ligands, antibodies, or peptides, they can precisely deliver drugs to specific cells, tissues, or receptors in the layers of skin. These surface modifications involve attaching molecules that can identify and attach to receptors or antigens on target cells. As a result, nanocarriers gather specifically at the site where they're needed. This targeted delivery method improves how well drugs work by focusing their effects exactly where they're supposed to be, cutting down on how much of the drug goes through the whole body and reducing any unintended effects5, 6.
Types of Nanocarriers in TDDS
Fig. 2: Functional Nano-systems used in transdermal drug delivery
Advantages of Nanocarrier-Based TDDS
Nanocarrier-based transdermal drug delivery systems (TDDS) provide number of advantages over conventional drug delivery methods. These include enhanced drug penetration, precise and sustained release, targeted delivery to specific sites, minimized side effects, and improved stability. These benefits collectively enhance the effectiveness and safety of transdermal therapeutic applications.
One of the primary challenges in TDDS is the skin's barrier function, particularly the stratum corneum, that limits the penetration of many drugs. Nanocarriers such as liposomes, niosomes, and nanoparticles can enhance drug penetration through interaction with the lipid matrix of the stratum corneum. This interaction disrupts the barrier, facilitating deeper and more efficient drug permeation. Additionally, the small size of nanocarriers allows them to navigate through skin pores and hair follicles, further enhancing drug delivery to the targeted site.
Nanocarriers allow us to regulate how drugs are released, making sure they're released slowly over time. This means patients can benefit from a steady and lasting treatment effect. By controlling how drugs are released, we can reduce how often patients need to take medication, making it easier for them to stick to their treatment plan. For example, technologies like solid lipid nanoparticles (SLNs) and polymeric nanoparticles can be designed to release drugs gradually, ensuring that drug levels in the body or specific tissues remain stable. This is especially helpful for conditions that need ongoing treatment over a long period.
Nanocarriers offer the capability to regulate the release rate of the enclosed drug, ensuring a steady and prolonged therapeutic effect. This controlled release mechanism decreases the frequency of drug administration, thereby enhancing patient compliance. For example, solid lipid nanoparticles (SLNs) and polymeric nanoparticles can be engineered to release drugs over an extended duration of time, maintaining consistent drug levels in the bloodstream or targeted tissues. This feature is particularly beneficial for chronic conditions requiring long-term medication.
Nanocarriers can be customized with special molecules like ligands, antibodies, or peptides that attach to receptors on specific cells or tissues. This targeted delivery method concentrates the drug exactly where it's needed, boosting its effectiveness and reducing its spread throughout the body. For instance, dendrimers can be tailored to deliver drugs precisely to affected areas, minimizing unintended side effects. This precision is especially critical in conditions such as cancer, where it's important to maximize drug impact on tumors while minimizing harm to healthy tissues.
By enabling targeted delivery and controlled release, nanocarrier-based TDDS significantly reduce the likelihood of systemic side effects. Traditional systemic drug delivery often results in drug distribution throughout the body, affecting healthy tissues and causing undesirable side effects. Nanocarriers, by concentrating the drug at the specific site of action and releasing it in a controlled manner, minimize these adverse effects. This reduction in side effects is especially important for potent drugs with narrow therapeutic windows, enhancing patient safety and treatment tolerance.
Nanocarriers shield drugs from environmental factors like light, oxygen, and moisture, which can degrade them over time. This protection enhances the stability and extends the shelf life of the drugs. For example, liposomes and polymeric nanoparticles safeguard drugs from enzymatic breakdown and water-based degradation, ensuring they remain potent until they reach their intended destination in the body. This enhanced stability not only prolongs the drug's effectiveness but also guarantees that patients receive the correct dosage for optimal therapeutic benefits15, 16.
Challenges and Limitations
While nanocarrier-based transdermal drug delivery systems (TDDS) offer numerous advantages, they also face several challenges and limitations that can hinder their development and widespread use. These challenges include skin irritation and toxicity, complex manufacturing processes, regulatory hurdles, scalability issues, and limited drug loading capacity. It is essential to address these issues for the effective integration of nanocarrier-based transdermal drug delivery systems into clinical practice.
One of the primary concerns with nanocarrier-based TDDS is the potential for skin irritation and toxicity. Nanocarriers, especially those containing surfactants or certain polymers, can cause skin irritation or allergic reactions. For instance, niosomes and some polymeric nanoparticles might induce inflammatory responses or disrupt the skin's natural barrier function, leading to redness, itching, or swelling. Additionally, the long-term safety of repeated exposure to nanocarriers remains a concern, as chronic use might lead to cumulative toxicity. Therefore, extensive biocompatibility testing and optimization of nanocarrier formulations are essential to minimize adverse skin reactions.
The production of nanocarriers involves sophisticated and intricate manufacturing processes that require precise control over several parameters, like particle size, surface charge, and drug encapsulation efficiency. Techniques like high-pressure homogenization, solvent evaporation, and self-assembly are often employed, each with its own set of challenges in terms of reproducibility and scalability. Ensuring consistent quality and batch-to-batch uniformity is critical but can be difficult to achieve due to the complexity of these processes. Moreover, the requirement for sterile production environments and stringent quality control measures adds to the manufacturing complexity and cost.
The regulatory landscape for nanocarrier-based TDDS is still evolving, and obtaining approval for these advanced drug delivery systems can be challenging. Regulatory agencies such as the FDA and EMA require comprehensive data on the safety, efficacy, and quality of nanocarrier formulations. This involves comprehensive characterization of the nanocarriers, along with in vitro and in vivo toxicity studies, and clinical trial data demonstrating therapeutic benefits and safety profiles. The lack of standardized guidelines and the novelty of nanotechnology-based products add to the regulatory complexity, potentially delaying market approval and increasing development costs.
Scaling up the production of nanocarrier-based TDDS from laboratory to industrial scale poses significant challenges. The precise conditions required for the synthesis and formulation of nanocarriers, such as temperature, pressure, and solvent composition, can be difficult to replicate on a larger scale. Additionally, maintaining the uniformity and consistency of nanocarrier properties, such as size distribution and drug loading, becomes more challenging with increased production volumes. Overcoming these scalability issues requires the development of robust, scalable manufacturing processes and technologies that can produce nanocarriers with consistent quality and performance.
Despite their advantages, many nanocarriers face limitations in their drug loading capacity. The amount of drug that can be encapsulated within a nanocarrier is often restricted by the carrier's size, surface area, and structural properties. For example, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) may have limited space for drug incorporation because of their solid lipid matrix. This limitation can be particularly problematic for high-dose drugs or those requiring sustained release over extended periods. Developing strategies to enhance drug loading capacity, such as optimizing carrier composition or using combination carriers, is necessary to overcome this limitation17, 18, 19.
Clinical Applications and Therapeutic Areas
Transdermal drug delivery systems (TDDS) utilizing nanocarriers have been explored in various clinical applications and therapeutic areas as they are capable to enhance drug penetration, provide controlled release, and minimize systemic side effects. Here are some key therapeutic areas where nanocarrier-based TDDS have shown promise:
Using patches to deliver painkillers through the skin offers a non-invasive way to manage chronic pain. Tiny carriers like liposomes and solid lipid nanoparticles can package drugs such as lidocaine and ibuprofen, helping them get through the skin better and providing long-lasting pain relief. For instance, special liposome versions of lidocaine have been created to keep an area numb for longer, which means fewer times you have to put it on and easier for patients to follow the treatment plan. Also, scientists are looking into nanoparticles that carry non-steroidal anti-inflammatory drugs (NSAIDs) to see if they can reduce swelling and pain without causing as many stomach problems. This shows how new technology could make pain treatments work better and be easier on your body20.
Hormone replacement therapy often involves administering hormones such as estrogen, progesterone, and testosterone. Transdermal delivery can be advantageous for these hormones to avoid being broken down in the liver initially and to maintain steady levels in the bloodstream. Nanocarrier-based transdermal drug delivery systems (TDDS) can improve how well these hormones dissolve and remain stable. For example, patches that contain estradiol enclosed in niosomes have proven to release hormones steadily, keeping hormone levels effective and managing symptoms of menopause better. Similarly, researchers are investigating liposomal forms of testosterone for conditions like hypogonadism, aiming to deliver hormones in a controlled and consistent manner21.
Nanocarrier-based TDDS are particularly advantageous for treating skin conditions due to their ability to target specific skin layers and enhance drug absorption. Conditions like psoriasis, eczema, and acne can benefit from nanocarrier systems that deliver therapeutic agents directly to the affected areas. Liposomes and niosomes are commonly used to encapsulate corticosteroids, retinoids, and antimicrobial agents, improving their therapeutic efficacy while reducing systemic side effects. For example, liposomal formulations of tacrolimus have been developed for atopic dermatitis, offering enhanced skin penetration and prolonged anti-inflammatory effects22.
Nanocarrier-enhanced transdermal drug delivery systems (TDDS) offer a non-invasive approach to administration of anticancer drugs directly to tumors, which reduces overall toxicity and enhances treatment effectiveness. Nanoparticles such as liposomes, dendrimers, and polymeric nanoparticles can be customized to target cancer cells specifically, increasing the concentration of drugs at tumor sites. For example, transdermal patches loaded with chemotherapy drugs like 5-fluorouracil (5-FU) have been studied for treating skin cancers, providing localized and controlled release of medication. Additionally, ongoing research aims to develop transdermal systems capable of delivering combination therapies, which could potentially improve the overall outcomes of cancer treatment23.
Examples of Specific Drugs/Formulations Used in Clinical Applications:
Future Prospects:
The future of nanocarrier-based transdermal drug delivery systems (TDDS) is bright, with several promising advancements on the horizon. These advancements include the development of smart nanocarriers, personalized medicine approaches, combination therapies, advanced characterization techniques, and regulatory harmonization. Each of these prospects holds the potential to significantly enhance the efficacy, safety, and versatility of TDDS.
One of the most exciting advancements in nanocarrier-based transdermal drug delivery systems (TDDS) is the development of smart nanocarriers. These are designed to react to specific triggers like pH, temperature, light, or enzymes, releasing their payloads in a targeted and controlled manner. For example, nanoparticles sensitive to pH changes can release drugs in response to the acidic conditions found in inflamed or cancerous tissues, ensuring that treatments are delivered precisely where they're needed. Similarly, temperature-sensitive liposomes can release their contents when they reach a particular temperature, which can be controlled externally through localized heating. This responsiveness enables more accurate drug delivery, reducing side effects and maximizing therapeutic benefits.
Personalized medicine aims to customize treatments for individual patients by considering their genetic, environmental, and lifestyle factors. Nanocarrier-based TDDS can play a crucial role in this approach by enabling the customization of drug delivery systems to meet the specific needs of patients. By using patient-specific data, such as genetic profiles and disease markers, nanocarriers can be engineered to deliver personalized doses and combinations of drugs, enhancing treatment outcomes. For example, personalized transdermal patches could be developed to release specific hormones or pain medications at tailored rates, optimizing therapeutic effects and reducing adverse reactions. This approach aligns with the broader trend in healthcare towards precision medicine, where treatments are increasingly individualized.
The use of combination therapies, where multiple drugs are delivered simultaneously to target different aspects of a disease, is gaining traction in medical research. Nanocarrier-based TDDS are well-suited for this purpose, as they can encapsulate multiple drugs within a single carrier, ensuring synchronized delivery. This is particularly valuable in cancer therapy, where combining chemotherapeutic agents with immunomodulators or targeted therapies can enhance treatment efficacy and reduce resistance. For instance, nanostructured lipid carriers (NLCs) can be designed to co-deliver chemotherapeutic drugs and anti-inflammatory agents, providing a synergistic effect that improves patient outcomes. The ability to fine-tune the release profiles of each drug further enhances the therapeutic potential of combination therapies.
The development and optimization of nanocarrier-based TDDS require sophisticated characterization techniques to ensure quality, safety, and efficacy. Advances in analytical methods, such as high-resolution microscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, are enhancing our ability to analyze nanocarriers at the molecular level. These techniques provide detailed insights into the size, morphology, surface properties, and drug encapsulation efficiency of nanocarriers, enabling precise control over their formulation. Additionally, in vitro and in vivo imaging techniques, such as confocal microscopy and MRI, allow for real-time tracking of nanocarrier distribution and drug release, facilitating the optimization of delivery systems.
The regulatory landscape for nanocarrier-based transdermal drug delivery systems (TDDS) is intricate and evolving, with different countries and regions having diverse approval requirements. Regulatory harmonization endeavors to standardize evaluation and approval processes for nanomedicines, thereby decreasing time and costs involved in introducing new products to the market. International collaboration among regulatory agencies, such as the FDA, EMA, and WHO, is essential to develop consistent guidelines and standards for nanocarrier-based TDDS. Harmonized regulations would ensure that these advanced delivery systems meet the highest safety and efficacy standards while facilitating global access to innovative treatments. Efforts to establish clear guidelines for the characterization, manufacturing, and clinical testing of nanocarriers are crucial for their successful commercialization.
Advances in nanocarrier materials are focusing on enhancing biocompatibility and biodegradability. Biocompatible polymers such as poly (lactic-co-glycolic acid) (PLGA), chitosan, and hyaluronic acid are being explored to minimize immune responses and toxicity. Biodegradable nanocarriers ensure that they degrade into non-toxic byproducts after delivering the drug, reducing the need for removal or disposal. This advancement is crucial for long-term applications and sustained release therapies where chronic exposure to non-biodegradable materials may pose risks.
Innovations in nanocarrier design aim to improve targeting capabilities through more precise ligand conjugation, enhanced receptor affinity, and responsiveness to microenvironmental cues in specific tissues or cells. These advancements are particularly beneficial in oncology and neurological disorders, where targeted drug delivery can improve efficacy and reduce systemic side effects.
Nanocarrier-based TDDS are expanding into the treatment of non-communicable diseases (NCDs) such as cardiovascular diseases, diabetes, and respiratory conditions. These advancements aim to improve disease management through enhanced drug efficacy, reduced dosing frequency, and improved patient compliance, thereby addressing the global burden of NCDs.
Research efforts are focusing on developing environmentally friendly nanocarriers that minimize ecological impact throughout their lifecycle, from synthesis to disposal. Sustainable nanocarriers reduce energy consumption, waste generation, and environmental pollution associated with conventional drug delivery systems, aligning with global sustainability goals25, 26, 27.
CONCLUSION:
Nanocarrier-based transdermal drug delivery systems (TDDS) offer a host of benefits, including improved drug penetration, precise and sustained release, targeted therapy, reduced side effects, and enhanced stability. These systems utilize a variety of nanocarriers such as liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, dendrimers, and hydrogels, making them adaptable for diverse clinical applications. Currently, nanocarrier-based TDDS are advancing in fields like pain management, hormone replacement therapy, dermatology, cancer treatment, and vaccination, showcasing their potential for effective and patient-friendly treatments. However, challenges such as skin irritation, complex manufacturing processes, regulatory requirements, scalability issues, and limited drug loading capacities need to be addressed for widespread adoption.
Looking forward, the development of smart nanocarriers that respond to specific stimuli will enable precise and controlled drug delivery. Personalized medicine approaches will customize treatments to meet individual patient needs, while combination therapies will capitalize on synergistic drug effects for improved outcomes. Advances in characterization techniques will refine these systems, and regulatory harmonization will streamline approval processes, paving the way for broader clinical use. Ongoing research and development are essential to addressing current challenges and maximizing the potential of nanocarrier-based transdermal drug delivery systems (TDDS). By fostering innovation and interdisciplinary collaboration, these advanced drug delivery systems can be optimized to enhance patient outcomes and revolutionize the field of drug delivery.
REFERENCE
1. Kumari P, Pathak K, Yadav J. Recent advancements in transdermal drug delivery systems: A review. Biomaterials Res. 2022;26(1):1-20. 2. Kumar A, Kumar A. Innovations in transdermal drug delivery systems: A comprehensive review. Indian J Pharm Sci. 2022;84(1):5-14. 3. Rao R, Naidu R. Overcoming challenges in transdermal drug delivery. J Adv Pharm Technol Res. 2023;14(1):45-55. 4. Kango S, Kalia S, Celli A, Njuguna J, Habibi Y, Kumar R. Surface modification of inorganic nanoparticles for development of organic–inorganic nanocomposites—A review. Prog Polym Sci. 2013;38(8):1232-1261. 5. Kumar P, Chhibber S, Mahajan R. Nanotechnology-based approaches for transdermal drug delivery: A comprehensive review. J Drug Deliv Sci Technol. 2023; 67:102932. 6. Sharma A, Garg T. Recent advancements in nanotechnology-based transdermal drug delivery systems. Expert Opin Drug Deliv. 2024;21(3):297-312. 7. Zeb A, Malik M, Shah F. Potential of nanoparticulate carriers for improved drug delivery via skin. J Pharm Investig. 2018; 49:485-517. 8. Gupta R, Sharma P. Recent developments in liposomal drug delivery systems for transdermal applications. Int J Pharm. 2024; 617:121639. 9. Singh A, Kaur H. Recent advances in niosomal drug delivery systems for transdermal applications. Asian J Pharm Sci. 2022;17(3):456-470. 10. Kumar P, Gupta R. Solid lipid nanoparticles: An efficient nanocarrier for transdermal drug delivery. Indian J Pharm Sci. 2022;84(3):221-232. 11. Patil A, Deshmukh T. Nanostructured lipid carriers: A novel approach for transdermal drug delivery. Indian J Pharm Sci. 2022;84(4):332-345. 12. Kumar S, Gupta N. Polymeric nanoparticles for transdermal drug delivery: Design, characterization, and applications. J Pharm Biomed Anal. 2024; 233:115304. 13. Patel M, Shah R. Dendrimers: Promising nanocarriers for transdermal drug delivery. Indian J Pharm Sci. 2022;84(6):567-582. 14. Reddy A, Gupta V. Hydrogels for transdermal drug delivery: Recent advancements and future prospects. Indian J Pharm Sci. 2022;84(7):634-649. 15. Patel D, Gupta R. Enhancing transdermal drug delivery with nanocarriers: A comprehensive review. Indian J Pharm Sci. 2022;84(5):456-472. 16. Kumar A, Verma S. Nanocarrier-mediated transdermal drug delivery: Mechanisms and clinical applications. J Pharm Biomed Anal. 2024; 234:115308. 17. Patel R, Desai A. Skin irritation and toxicity concerns in nanocarrier-based transdermal drug delivery systems. J Pharm Sci. 2022;110(4):1523-1531. 18. Sinha P, Joshi R. Challenges in the manufacturing of nanocarriers for transdermal drug delivery. Int J Pharm. 2023; 607:120979. 19. Sharma R, Mehta P. Innovations in manufacturing processes for nanocarrier-based drug delivery. J Pharm Innov. 2023;18(1):78-87. 20. Sharma P, Singh J. Liposomal lidocaine for enhanced pain management: A review. Indian J Pain. 2021;35(2):120-127. 21. Verma S, Gupta R. Niosome-based transdermal delivery of estradiol: Formulation and clinical outcomes. J Pharm Sci. 2023;112(4):983-992. 22. Kaur P, Malhotra S. Liposomal tacrolimus in atopic dermatitis: Clinical efficacy and safety. Indian J Dermatol Venereol Leprol. 2021;87(6):765-772. 23. Roy S, Banerjee A. Transdermal delivery of 5-fluorouracil using polymeric nanoparticles: A clinical perspective. Cancer Nanotechnol. 2022;13(1):45-55. 24. Singh N, Kapoor G. Polymeric nanoparticles for transdermal delivery of influenza vaccines: Current status and future perspectives. J Immunol Res. 2022; 2022:1-11. 25. Garg B, Jain A, Singh S. Smart nanocarriers: A promising approach for transdermal drug delivery systems. Int J Nanomedicine. 2023; 18:325-340. 26. Sharma R, Gupta S, Aggarwal G. Personalized medicine in transdermal drug delivery: Current status and future perspectives. Drug Deliv Transl Res. 2022;12(2):308-325. 27. Kulkarni S, Deshmukh R, Patil A. Advanced characterization techniques for evaluating nanocarrier-based transdermal drug delivery systems. J Pharm Sci. 2024;113(5):1506-1522.
10.5281/zenodo.12806579
