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Department of Pharmaceutics, KMCH College of Pharmacy, Kovai Estate, Kalapatti Road, Coimbatore – 641048, Tamil Nadu, India.Affiliated to The Tamil Nadu Dr. M.G.R. Medical University, Chennai, Tamil Nadu, India.
Psoriasis is a recurrent immune-mediated inflammatory skin disease with the pathophysiology of dysregulated proliferation and IL-23/Th17 axis activation of keratinocytes, which results in reddening and scaly patches on the skin, as well as extra-cutaneous comorbidities. Topical treatments such as conventional ones rarely have an effective solution in that they are not aqueously soluble, lack absorption through skin, and are blocked by tougher keratinocytes in psoriatic lesions. Topical cationic drug delivery systems based on nanocrystals have emerged as an alternative, promising approach to overcome these shortcomings, as nanocrystals increase drug dissolution, saturation solubility, and dermal bioavailability. This review provides a comprehensive overview of nanocrystal fabrication processes, both top-down processes like wet milling and high-pressure homogenization, and bottom-up processes like antisolvent precipitation. The role of stabilizers, such as surfactants and polymers, in ensuring physicochemical stability and anti-aggregation is explained. In psoriasis, nanocrystal formulations have shown better stickiness to skin and the capacity to conquer the stratum corium and extend retention of drugs, hence leading to better therapeutic effects. Although these benefits exist, there are several challenges, such as physicochemical instability (e.g., Ostwald ripening, aggregation), scale effects, regulatory uncertainty, and translatability to the clinic. Issues of nanotoxicity, patient compliance, and cost-effectiveness further discourage universal implementation. The prospects are in the implementation of nanocrystals with improved delivery systems in the form of liposomes, hydrogel, and microneedles, and the construction of stimuli-responsive and targeted systems. The new technologies that will transform psoriasis treatment include AI-driven formulation design, personalized medicine, CRISPR-based gene delivery, digital twin modelling. Therefore, this review aims to provide a comprehensive and critical analysis of nanocrystal-based topical drug delivery systems in psoriasis management, focusing on fabrication techniques, stabilization strategies, therapeutic applications, limitations, and future perspectives.
Psoriasis is an immune-mediated and chronic inflammatory disorder of the skin, which is the abnormal growth of keratinocytes and the incessant inflammation that causes scaly erythema1. Its pathogenesis is a complicated interplay between genetic predisposition, environmental triggers, and immune dysregulation with the predominant subsidiary activity of the IL- 23/ Th17 axis 2. The IL-23 secretion elicited by the activation of dendritic cells results in Th17 cell differentiation and the subsequent release of pro-inflammatory cytokines, including IL-17, IL-22, and TNF-α, that promote the acceleration of the keratinocyte proliferation and maintain inflammatory cascades1,2. Keratinocytes also increase this response by the release of immune cell-recruiting chemokines, continuing to develop the disease3. Psoriasis has a histologic appearance of epidermal hyperplasia and parakeratosis and neutrophil buildup (Munro microabscesses), and the epidermal turnover time of psoriatic skin is significantly decreased in relation to the normal skin4,5. Aiming to affect about 2-3 per cent of the world population, psoriasis also comes with systemic comorbidities, such as psoriatic arthritis and cardiovascular disorders 5. Although it is a first-line intervention, standard topical techniques have poor benefits owing to compromised barrier functions and hyperkeratosis. Studies in nano-crystallization-based delivery systems provide an effective approach because they allow better solubility, skin adhesion, and penetration of the drug and thus generate a better localized therapeutic effect and reduce systemic exposure 6.
Fabrication Techniques
Nanocrystals have become one of the new approaches to improve the solubility, dissolution rate, and bioavailability of poorly water-soluble drugs. Processes of drug nanocrystals preparation have tended to be based on two major strategies: top-down, in which large drug particles are scaled down to nanoscale dimensions, and bottom-up, in which nanocrystals are prepared by crystallization of molecular solutions 7. These fabrication techniques are important in defining the size of fabricated particles, their stability, and their performance in delivering therapeutic properties on topical preparations by means of nanocrystals.
Wet Milling
One of the most popular top-down methods for the creation of pharmaceutical nanocrystals is wet milling (also known as media milling or bead milling). During the process, coarse-sized drug particles are suspended in a liquid medium that contains stabilizers and then exposed to mechanical reduction of the size of the particles using milling beads 8. Milling chamber beads used are usually composed of zirconium oxide, stainless steel, glass, or crosslinked polymer resins. The reduction in size of the particles is because of repeated collisions of drug particles with the milling beads and shear forces created in the milling chamber.
The wet milling process involves continuous mixing of the suspension of the drug, which leads to breaking of the particles due to mechanical impact and friction. These forces slowly influence the size of the participants to the nanometer dimension. The nanosuspension is physically stabilized through the addition of stabilizers, including surfactants and polymers, in the milling process to prevent aggregations.
The use of wet milling has been effective in the formulation of dermal nanocrystals. Wet bead milling has been used to prepare miconazole nitrate nanosuspensions, which have been discovered to be superior in terms of antifungal activity and penetration on the skin. Surfactants like poloxamer 407 and Tween 80 were used in this study to stabilize and obtain the nanosuspension of the material suitable for achieving a stable nanocrystal with the best particle size and dispersion behavior.
For consistent sizing of the nanocrystals (uniform particle diameter) and stabilization of the nanocrystals, optimization of milling parameters is necessary. Milling time, bead size, stabilizer concentration, and temperature are some of the factors that determine the final particle characteristics. Over milling due to excess: An excessive milling process can cause Ostwald ripening or the generation of crystals, which can decrease the stability of a formulation as well as its therapeutic performance. Thus, a wise choice of parameters of formulation and processing in the wet milling process is required7,8.
The use of wet milling is highly favored in the pharmaceutical industry development due to the ability to produce the nanosuspension on a large scale and the ability of the method to produce high drug content in the nanosuspensions. The technique has become so popular in the manufacturing of commercial nanocrystal-based formulations owing to these benefits.
High-Pressure Homogenization
Another commonly used top-down technique for producing drug nanocrystals is high-pressure homogenization (HPH). This method involves pumping of a coarse drug suspension through a fine homogenization orifice under very high pressure, ranging from 100 to 2000 bar. The acceleration and the high rate at which pressure decreases produce high mechanical actions in the form of shear stress, cavitation, and collisions of particles, which help in the reduction of the particle size 9.
In the homogenization process, the suspension is subjected to several homogenization processes until the size of the suspended particles attains a nanoscale size and fine size distribution. Cavitation is a major determinant in the reduction of the size of the particles. The pressure changes make the vapour bubbles when the suspension passes through the homogenizer gap and bursts. The bursting of such bubbles creates a shock wave, which breaks the drug particles into nanocrystals.
One of the benefits of high-pressure homogenization is the capacity to obtain stable nanosuspensions with a homogeneous distribution of particle size. The process can also be applied to a large-scale manufacturing operation, and has found extensive application in the pharmaceutical industry to enhance the solubility rate and bioavailability of poorly soluble drugs.
To enhance the efficiency, high-pressure homogenization, in many instances, is use for other methods of preparation of nanocrystals. Among them is the Nano Edge technology, a combination of precipitation and homogenization. In this method, primary crystal particles are created through precipitation, and post-homogenization of high pressure is used to minimize the size of the crystals as well as inhibit the formation of secondary crystals. Such a combination helps to increase the consistency of particle size and physical stability of nanocrystals.
Smart Crystal® technology is another advanced method where a pre-treatment step (wet milling, spray drying, freeze drying or precipitation) is applied, and thereafter high-pressure homogenization is done 10. The technology has been termed the second-generation nanocrystal production methodology and enables particle-size minimization by leveraging various supporting processes. High-pressure homogenization is one of the most frequently used techniques of producing nanocrystals industrially because of its high cost-effectiveness and scalability.
Antisolvent Precipitation
One of the most popular bottom-up methods applied in the production of drug nanocrystals is antisolvent precipitation. In comparison with top-down approaches, this is based on the creation of nanocrystals by using molecular drug solutions based on managed crystallization. Under this technique, the solubility-poor drug is initially dissolved in some appropriate organic solvent and is then speedily blended with a non-solvent (antisolvent), with the drug being of exceptionally minimal solubility.
Solvent and antisolvent rapidly blend, resulting in a process known as supersaturation, initiating the nucleation and the creation of nanocrystals. It occurs in two broad steps, namely nucleation and crystal growth. The nucleation process involves the formation of small crystal nuclei by the rapid aggregation of drug molecules together and crystal growth 10,9, in which the formation of crystals is the formation of a stable nanocrystal. The addition of stabilizers is normally done in the process to avoid aggregation and manage the growth of crystals.
Antisolvent precipitation is associated with several merits, such as ease, low cost, and the capability to obtain nanocrystals of high-quality regarding size distribution. The technique has found extensive applications in the synthesis of different drugs in nanocrystal form to enhance their solubility and dissolution speed.
Several sophisticated methods of antisolvent precipitation have been invented. As an example, the high-gravity antisolvent precipitation (HGAP) can be used to allow continuous formation of nanocrystals with uniform size distribution and better recovery rate. Equally, evaporative precipitation to aqueous solution (EPAS) defines the formation of nanoparticles with a high dissolution rate because the nanoparticles have a small size and low crystallinity 9,8.
These sophisticated methods show how bottom-up methods are versatile in the development of nanocrystal preparations that would have a better pharmaceutical profile.
Nanocrystal Formulations: Key Excipients and Stabilizers.
The stabilizers play a vital role in nanocrystal systems as they allow the non-aggregation of particles as well as physical stability in the nanosuspension. Nanocrystals tend to grow and form during storage because of the very high surface energy of the crystals. This instability can be limited by stabilizers which enhance a steric or electrostatic repulsion between the particles.
Fig. 1 Schematic representation of nanocrystal fabrication techniques, including wet milling (showing shear forces from milling media reducing drug particles to nanocrystals), antisolvent precipitation (depicting rapid nucleation upon solvent mixing), and high-pressure homogenization 6,11,24,26 (illustrating cavitation and shear through narrow gaps) Created using AI-assisted visualization tools for conceptual illustration only. Source: Created by the authors based on information compiled from Refs. 6, 11, 24, 26, and 29.
Surfactants
The most typical stabilizers in nanocrystal preparations are surfactants, as these adsorb onto the tablet surface of drug particles and decrease the interfacial tension between the drug and the dispersion media. Surfactants ensure nanoscale dispersion of nanocrystals by creating an adsorption layer around them to prevent their aggregation 11. Popular surfactants in formulations of nanocrystals are Tween 80, poloxamer 188, plus poloxamer 407. These surfactants offer a steric stabilization force that is created by creating a protective coating on the crystal surface. Surfactants like poloxamer 407 and tween 80 were identified to stabilize nanosuspension in miconazole nitrate nanocrystal formulations to give particle sizes of approximately 350 nm 9,11. These stabilizers ensured that the crystals did not form aggregates, and even after storage, the particle size in the nanoscale was maintained. Also, surfactants enhance dissolution rate, skin penetration, and drug wetting and dispersion to improve wetting and dissolution rates of the drug when used in topical preparations 10.
Polymers
Nanocrystal-based preparations can also contain polymeric stabilizers to attain steric stabilization. The polymers adsorb to the surface of nanocrystals, forming a protective layer, which does not allow the particles to encounter each other and thus to form aggregates.
Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and polyvinylpyrrolidone (PVP) are examples of commonly used polymeric stabilizers. These polymers enhance the physical stability of nanosuspensions and aid in the preservation of particle size distribution storage. In other instances, polymeric stabilizers can exhibit higher adsorption to the crystal surface than low-molecular-weight surfactants 9,11. As an example, poloxamer 407 is capable of binding to the crystal surface in more than one interaction site, eliminating this to the nanocrystals and enhancing nanocrystal stabilization.
Effects of Stabilizers on the Stability of Nano Crystals
The performance and stability of nanocrystal formulations majorly depend on the type and concentration of stabilizers. Controlling particle size distribution, surface charge and crystal growth resistance or aggregation is done by stabilizers 12,13. Electrostatic stabilization forms when polarizing agents create repulsion between particles, where steric stabilization forms when polymer chains create a physical barrier against contact between particles. A mixture of the two mechanisms is optimal in terms of stability in most formulations 13. The appropriate choice of stabilizer is thus essential in the maintenance of the nanoscale size of the particle and inhibition of instability processes like aggregation or Ostwald ripening with the course of storage.
Remarkable Nanocrystal Formulations of Topical Delivery
The application of nanocrystals has received a lot of research in the advancement of topical delivery of drugs that are poorly soluble. A smaller particle size down to a nanometer scale means that the surface area of the drug grows exponentially, which leads to a higher rate of dissolution and, therefore, improved skin penetration. As an illustration, the nanocrystals of miconazole nitrate produced under the wet bead milling technique exhibited better antifungal as well as dermal penetration effects relative to the traditional formulations 11,12. There were increased inhibition regions of nanosuspension against C.albicans, which showed increased antifungal resistance. The development of nanocrystals has also been examined in the use of anti-inflammatory and dermatological. The increased aqueous solubility and the adhesive properties of the nanocrystals are found to increase the therapeutic effect and the prolonged residence time of the drug on the skin surface. Moreover, the particle size at the nanoscale elevates concentration between the formulation and the skin 10, which enhances the diffusion of drugs into the deeper layers of the skin. Consequently, the formulations based on nanocrystals have demonstrated high potential regarding the better outcomes of topical treatment of skin disorders.
Challenges and Limitations
Physicochemical Hurdles
High surface free energy of nanocrystal-based drug delivery systems results in physicochemical instability because of crystal growth and Ostwald ripening. With smaller particles, the particles dissolve and redeposit to the larger particles, causing an increase in the particle size as well as an efficiency of that dissolution 13-15. This is very unstable, and thus it does compromise long-term storage and therapeutic performance. The other significant constraint is aggregation and agglomeration, which is a result of a lack of sufficient steric or electrostatic stabilization. The misuse of stabilizers in terms of type or concentration results in clustering of particles, which causes a decrease in real surface area and bioavailability 16-17. The condition is also worsened in the lyophilization and spray drying process and leads to poor redispersibility 18. The nanocrystals are also susceptible to polymorphic and crystallinity changes, particularly upon storage. The changes modify solubility and dissolution characteristics and cause differences in drug performance 19. Also, there is the occurrence of sedimentation and flocculation because of an imbalance between the force of gravity and the force between particles, especially in nanosuspensions 20.
Zeta potential and stability are affected by the environmental factors that include pH, ionic strength, and temperature; thus, nanocrystal systems are highly sensitive to environmental factors 21. The process of stabilizer screening is not only important but also difficult because there are no predictive models to assess the interactions of nanoparticles.
Regulatory and Scalability Issues
It is a hard attempt to scale nanocrystal production to an industrial level after having achieved it at the laboratory level. Wet milling techniques and high-pressure homogenization are extremely process parameter-sensitive, and thus batch-to-batch reproducibility is a challenging idea 22,23. Any change in pressure, temperature, or milling time can lead to a major change in particle size and distribution. The other important concern is that it is contaminated by milling media that can add impurities and can also interfere with the safety of the products. This creates some apprehensions with respect to abiding by regulation and quality assurance 24. Regulatively, the nanocrystals are regarded as complex systems because of their nanoscale characteristics. The regulatory bodies need thorough consideration of:
Nanotoxicity and biodistribution
Excipient safety
Stability during long-term in GMP conditions.
Yet, this lack of standardized regulation policies makes the way to approval more difficult 25. Also, nanocrystals require a high input of energy and specialized machinery, which escalates the process of manufacturing them. There is also the need to observe rigid compliance with Good Manufacturing Practice (GMP), which contributes to the complexity of operations and increases operational expenses 26. Environmental issues and solvent usage are other areas that create regulatory difficulties as well.
Clinical translation barrier
Nanocrystals have various challenges to clinical translation despite showing favorable results in preclinical studies. The lack of adequate clinical trials is one of the greatest limitations, as it limits the comprehension of long-term safety and efficacy. In topical drug delivery, the stratum corneum is a strong barrier, which does not easily allow the drug to penetrate despite the higher solubility of the nanocrystals 27-30. It is still difficult to reach a steady level of drugs in the deeper layers of skin.
Problems in the patient-related aspects include:
Skin irritation
Hypersensitivity reactions
Negative cosmetic acceptability
It has the potential to affect patient compliance negatively in chronic dermatological interventions 31-34. Nanotoxicity is also another key issue because nanocrystals may be able to interact with a biological system at the cellular level and can result in oxidative stress, inflammation, or cytotoxic effects 35,36. Lastly, cost-effectiveness is another important obstacle. The formulation is complex, production is costly, and the infrastructure is sophisticated, which places accessibility beyond the reach of people, especially in developing nations 37. Physiological differences that occur in the routes of administration also help in making clinical translation more complicated.
Table 1 presents a comparative analysis of nanocrystals, SLNs, and liposomes, highlighting their structural differences, drug-loading capacity, stability, and suitability for topical drug delivery applications 6,9,24,25,30,39 Source: Compiled by the authors from Refs. 6, 9, 24, 25, 30, 39.
FUTURE PERSPECTIVES
To curb such problems, several innovative approaches are under consideration. Stability and skin retention can be enhanced through development of hybrid delivery systems, i.e. nanocrystals into gels, hydro-gel, or lipid-based carriers. pH, temperature, or inflammatory-responsive systems do present desiccated chances to select different drug delivery to psoriatic lesions. Initial uses of artificial intelligence (AI) and machine learning in formulation design are becoming a potent approach to optimize the factors influencing a formulation, predict stability, and speed up development timelines. Also, the idea of personalized medicine, i.e. the ability to customize the formulations depending on severity of diseases and the skin peculiarities of a patient, is highly promising. There is a need to also undertake future studies that are well designed clinical trials, build regulatory frameworks and formulate standard evaluation protocols to be able to translate nanocrystal-based systems between laboratory and clinical practice.
Hybrid Systems Nanocrystals and Liposomes, Gels and Microneedles
The future development of nanocrystal-based drug delivery systems is more oriented towards hybrid systems, in which nanocrystals have been combined with lipid vesicles, polymeric gels, or microneedle systems, to address shortcomings of conventional delivery. Such hybrid systems will offer synergistic characteristics like increased drug loading, controlled release, and better skin pervaporation. Liposomes and niosomes with nanocrystals show marked benefits in the ability to readily target drugs at the dermal level and the capacity of carrying formerly hydrophilic drugs as well as lipophilic drugs 38-40. These hybrid lipid vesicles are more permeable and minimally exposed to the system, which is especially useful in chronic patients. Nanocrystal preparations of hydrogel derivatives also increase the residence time and local retention of drugs, which maintains sustained release and better patient compliance. These systems have other advantages, like the possibility to hydrate psoriatic lesions and decrease the irritation of the skin 41-43. Microneedle-aided delivery is a radical method of delivery that allows minimal and targeted transdermal delivery. Recent research shows that the use of nanocrystal-loaded dissolving microneedles and cubosome-integrated systems is significantly more effective in terms of drug penetration, better therapeutic effects, and systemic toxicity reduction. Also, microneedles make microchannels in the skin, which practically penetrate the stratum corneum barrier and enhance the drug bioavailability. In general, the hybrid nanocrystal systems are a viable approach towards employing multifunctional, targeted and patient-friendly systems of drug delivery.
Table 2 represents an overview of advanced nanocrystal-based hybrid and intelligent delivery systems, highlighting their design, mechanisms, advantages, limitations, and future potential in targeted dermatological therapy39,62,74,92,100 Source: compiled by authors from ref.39,62,74,92,100.
Intelligent and Stimulus Response Nanocrystal
Administration has recently been achieved with the help of stimuli-responsive nanocrystals developed by recent advances in nanotechnology, and can subsequently release drugs based on certain physiological stimuli such as pH, enzymes, temperature, or oxidative stress. The pathogenesis of psoriasis is characterized by changes in pH levels and enzyme activity of inflamed tissues of the skin, which makes it an optimal site of triggered drug release and increases the effect of the site-specific delivery of drugs and reduces their off-target toxicity 44-46. The activation of enzyme-responsive nanocrystals, which are directed by inflammatory enzymes (like proteases), enables directed local delivery and reduces toxicity in the system and enhances safety specifications 47. In addition, by linking nanocrystals to responsive polymers, it is possible to release drugs on demand and enhance accurate treatment. Targeting ligand-functionalized nanocrystals is also used to further improve cell-specific delivery, especially to keratinocytes and immune cells involved in the pathogenesis of psoriasis 48-51. There is also a current exploration of advanced Theranostics into which nanocrystals look to be capable of diagnostic and therapeutic functions, and in which real-time response of treatment is monitored52-55.
Emerging Trends: Customized Medicine, AI-optimized Doses and Nanotoxicology
The development of artificial intelligence (AI) and machine learning (ML) in nanocrystal formulation is transforming the sphere. Artificial intelligence (AI) based models can be used to forecast important parameters in formulation, including particle size, stability, and drug release kinetics, which consumes less time in the experimental process and improves the efficiency of formulation 56-62. It is also utilizing AI in conjunction with novel delivery technologies, including microneedles, to optimize mechanical strength, drug load, and release properties to achieve better therapeutic outcomes 62-68. Individual medicine is another considerable innovation, according to which prescriptions are developed, considering personal traits of the patient, such as genetic profile, severity of disease, and skin physiology. This method leads to an increase in the effectiveness of treatment and minimizes side effects 69. There has been a growing interest in nanotoxicology, which deals with the long-term safety and biology of nanocrystals. Investigations also give rise to the necessity of considering:
Cellular uptake mechanisms
Oxidative stress induction
Immunological responses to guarantee secure clinical translation
Regulatory frameworks are also evolving toward a safer-by-design nanomedicine policy whereby the nanocrystals are engineered to have the best safety and efficacy characteristics 70. Moreover, the use of interdisciplinary methods of combining nanotechnology, biotechnology, and computational devices will lead to the further development of drug delivery systems in the future.
The Next-Generation Innovations of Nanocrystal-Based Topical Drug Delivery
3D Bioprinting-Integrated Nanocrystal Systems
Recent developments in 3D bioprinting have also facilitated the production of patient personalized drug delivery circuits by the incorporation of nanocrystals in bioinks, which are competitive to biology. By these systems, it is possible to have accurate spatial control of drug distribution and release kinetics, which can subsequently be used to give specific therapy depending on the size and the severity of the lesions, such as psoriasis 71. Compared to the traditional hydrogels, 3D-printed nanocrystal scaffolds present regulated architecture, higher drug loading, and site-specific localization. The technology is a form of transformation to the individual and improves accuracy in dermatological treatment 72,73.
Nanocrystal Delivery based on Gene Editing (CRISPR Systems)
Disease-modifying therapies have now been made possible by the combination of nanocrystals with gene-editing applications like CRISPR/Cas9. Nanocrystals could be used to deliver nucleic acids (siRNA, mRNA, or CRISPR components), providing saturation of inflammatory signaling (Psoriasis treatment), such as IL-17, TNF-α. This strategy has the potential to shift away with the possibilities of symptomatic improvements to genetic control of the disease developments on a long-term basis 74-78.
Smart Wearable-based Delivery Systems
New intelligent delivery systems are incorporating nanocrystal preparations with wearable biosensors that can quantify physiological aspects of skin pH, temperature, and inflammatory biomarkers. They provide stimulus-stimulated drug delivery in real-time, creating a closed-loop therapeutic system. Such systems help to increase the level of accuracy in the treatment, minimize the loss of drugs, and improve the level of patient compliance compared to traditional delivery methods 79-81.
Biomimetic (Exosome-Coated) Nanocrystals
A new type of biomimetic nanocarrier, exosome-coated nanocrystals, has been noticed with its high biocompatibility and targeting capacity. Exosomes, as naturally occurring vesicles, increase immune evasion and cellular uptake in inflamed dermal tissues. These systems show better therapeutic results and decreased systemic poisoning when contrasted to synthetic microscales like liposomes and are eminent to the future of safe and efficient delivery of drugs 82-85.
Nanocrystals in response to External Stimuli
Nanocrystal systems are looking at advanced systems that are designed to react to external stimuli, including magnetic fields and ultrasound. Magnetic targeting facilitates the accumulation of drug carriers at sites, and ultrasound (sonophoresis) is a technique that improves skin permeability and the release of drugs. Such technologies enable the non-invasive administration of the drugs, which is much closer to the deep skin layers and as such, there is increased penetration and therapeutic performance 86-89.
Fig. 2 Schematic of an advanced nanocrystal-based topical drug delivery system integrating microneedles for mechanical penetration, smart polymers for stimuli-responsive release, and AI for optimization in psoriasis management 16,3941,45,47-49, Created using AI-assisted visualization tools for conceptual illustration only. Source: Created by the authors based on information compiled from Refs. 16, 39, 41, 45, 47–49
Digital Twin and Artificial Intelligence-delivered Predictive Modelling
Nanomedicine is adopting the idea of digital twin technology, where a virtual version of a patient is developed to mimic the effects of drug delivery. Through the combination of AI and patient information (skin type, the severity of the disease), scientists will be able to forecast the behavior of nanocrystals, more effectively design drugs, and individualize treatment plans. It reduces the trial-and-error experimentation and expeditiously translates into clinical 90-93.
Multi-Drug Co-Loaded Nanocrystal Systems
The harmonious, futuristic nanocrystal preparations are oriented towards combination therapy in which more than one drug (anti-inflammatory, immunomodulatory, and antioxidant agents) is concomitantly packed within the same carrier. The systems allow synergetic therapeutic effects, lower dosing rate, and enhance patient adherence. These multifunctional platforms are a major improvement over the single-drug delivery system 94,95.
Green Nanotechnology Methodologies
The development of nanocrystals in sustainable ways of fabrication is becoming common. They involve the use of biodegradable polymers, the use of plant stabilisers, and solvent-free preparation methods. Green nanotechnology has a higher level of environmental impact reduction besides increasing biocompatibility and regulatory acceptability, which resonates with the idea of safe-by-design nanomedicine 96-99.
DISCUSSION
Although nanocrystal-based topical drug delivery systems have highly promising potential to be used in managing psoriasis, there are a few critical challenges that prevent the wide scale use and commercial usability. Physical instability is one of the major issues because nanocrystals are characterized by a large surface energy, which carries a predilection towards aggregation, crystal growth (Ostwald ripening), and overtime sedimentation. Such instability may have profound impacts on the dissolution character and bioavailability of drugs and their general therapeutic action. Controversially, the choice and optimization of stabilizers are of paramount importance but when the concentration of the selected stabilizers is inappropriate, they might result in toxicity or minimal effect. A second critical drawback is that, although formulation-related issues are also a significant limitation due to disconnect also to large-scale production, uniform particle size distribution, and reproducibility are also problematic. Although processes like high-pressure homogenization and wet milling can be scaled, consistency in particle size and lack of contamination during the processing is a major challenge. Penetration and retention of skin is also a complex issue. Even though nanocrystals increase saturation solubility and the relocation of the crystals to the skin surface, their penetration is further controlled by stratum corneum barrier to a great extent. In heavily keratinized diseases like psoriasis, the approach may be further limited, as the penetration of drugs may require the use of penetration enhancers or necessitate the use of combination methods with other nanocarriers.
Regulatory wise, absence of well-developed guidelines on nanocrystal-based formulations is an obstacle to approval. Tight characterization of particle size, morphology, stability, and safety is requested by the regulatory agencies due to the widespread way nanomedicines are harmonized globally. Along with this, the safety data of nanoscale systems and toxicity distribution over a long period is not adequate particularly in chronic dermatological application.
Another bottleneck is scale-up and industrial feasibility. Even though nanocrystals are deemed to be relatively inexpensive to other types of NPs, batch-to-batch reliability, equipment expenses, process optimization also pose a bottleneck to industrial uptake. In addition, a lack of clinical evidence is also one of the gaps. Most of the research on nanocrystal-based topical systems remains limited to in vitro and preclinical research, with a relatively shortage of properly-designed clinical trials to support their effectiveness and safety in humans.
CONCLUSION
Topical delivery systems made of nanocrystals have become one of the viable approaches to addressing the shortcomings of such poorly soluble drugs in their dermatological applications. Nanocrystals greatly enhance the absorption of drugs through solubility, rate of dissolution, and skin penetration, thereby improving the bioavailability and treatment of diseases like psoriasis. They are also further improved by the incorporation of advanced formulation strategies such as integration of hydrogel, follicular targeting, and stimuli-responsive systems, which increase their clinical potential. Although all these have been implemented, it is important that concerns about scalability, stability, and safety evaluation are tackled so that successful translation into clinical practice can be achieved. Subsequent studies ought to include questions on how nanocrystal technology can be combined with other new techniques, including microneedles, artificial intelligence-based formulation development, and personalized medicine. To attain the full potential of the nanocrystal-based topical delivery systems, a multidisciplinary attack with a combination of formulation science, skin biology, and regulatory insights will prove to be effective in tackling the challenge of nanoparticle-based delivery systems.
REFERENCES
Sneha R., Yokeshwaran S., Dhanapriya S., Naresh Kumar S., C. Sankar, Emerging Nanocrystals-Based Topical Delivery Systems in Psoriasis Management: Advances, Challenges, Future Perspectives, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 7, 5090-5107, https://doi.org/10.5281/zenodo.21622761
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