Introduction

Over the past two decades, there has been a notable emergence of cutting-edge advancements in the realm of pharmaceutical research and development. The automation of the drug discovery process, facilitated by technologies such as high-throughput screening, combinatorial chemistry, and computer-aided drug design, has resulted in the generation of a substantial array of highly effective drug candidates.1 Regrettably, a considerable proportion of these promising medications grapple with the challenge of low water solubility, with approximately 40% of drugs in the developmental pipeline encountering solubility issues.2,3 High-throughput screening techniques have contributed to the identification of an increasing number of drugs exhibiting limited water solubility.

The constrained solubility of these compounds poses a significant impediment during the initial phases of screening for pharmacological activity, as well as throughout the formulation development and clinical testing processes.4 Preparing one of these substances for preclinical investigations and pharmacological activity assessments is a prerequisite well in advance of their commercialization.5 Consequently, it becomes evident that the adoption of innovative technical strategies is imperative to augment the bioavailability of drugs characterized by low solubility. The predominant challenge faced by the pharmaceutical industry resides in the development of novel formulation procedures and drug delivery technologies tailored to effectively address the solubility limitations associated with therapeutic candidates. These concerns frequently intersect with issues pertaining to low oral bioavailability.6–8 To attain optimal bioavailability for these medications, it is imperative to ensure their rapid absorption post-oral administration. The intravenous route represents an additional viable means of administration.9

Furthermore, various formulation strategies have been devised to address the challenges posed by poorly soluble medications, often referred to as “particular strategies”.10 The effectiveness of these approaches hinges on the specific chemical characteristics exhibited by molecules, encompassing factors such as their solubility in different organic solvents and distinctive attributes related to molecular size or configuration, such as molecules designed for incorporation into cyclodextrin ring structures.2,11 Undoubtedly, a more rational approach would involve the implementation of a “universal formulation approach” that can be applied to a wide range of molecules.

Micronization, the process of reducing the size of drug powders within the range of 1 to 10 μm, is a widely employed technique in pharmaceutical formulations aimed at augmenting the oral bioavailability of drugs. The formulation process discussed here is commonly employed with the objective of enhancing the oral bioavailability of pharmaceutical compounds.12,13 The insufficient solubility of frequently used medicines often restricts the effectiveness of micronization. Addressing the unresolved issues related to the bioavailability of drugs categorized under the biopharmaceutical specification class II, which are characterized by limited solubility, necessitates more than solely increasing the surface area to enhance dissolution rates.14

Building upon the concept of micronization, nanonization has emerged as a subsequent development. Since the 1990s, the field of nanosystems has advocated for the utilization of nanocrystals, rather than microcrystals, to improve the oral bioavailability of pharmaceuticals. Additionally, nanocrystals that can be dispersed in water, known as nanosuspensions, have found application in intravenous administration and pulmonary delivery of medications.15

Over the past two decades, drug nanocrystal technology has emerged as a prominent advancement in the pharmaceutical industry. One of the key advantages of developing drugs with low solubility lies in the technique it employs, which results in the creation of “nanosuspensions”. These nanosuspensions are essentially the dispersion of drug nanocrystals within a liquid medium, typically water.16–21 Nanosuspensions primarily comprise drug nanoparticles, typically ranging in size from 100 to 1000 nm. To maintain stability, these nanoparticles are supported by a small quantity of surface-active compounds.3,22

The skin serves as a crucial site for the painless and non-invasive administration of therapeutic substances, allowing for the control of their release and circumventing first-pass metabolism. Upon dermal absorption, medications can exert their effects locally, regionally, or systemically at various target sites.23,24 These considerations have led to the perception that drug delivery through the skin is a compelling yet challenging research area. The principal obstacle is overcoming the skin’s remarkable impermeability. The skin is a complex tissue that shields the body from invading pathogens, withstands chemical and physical assaults, and regulates essential functions such as temperature regulation.25 Its various anatomically distinct layers consist of the stratum corneum (SC), the accessible epidermis, and the dermis. The primary physical barrier is situated in the SC, composed of protein-rich dead cells (corneocytes with cornified cytoskeletal components and corneodesmosomes) and lipid-rich structures (lamellar sheets comprising roughly equimolar amounts of free fatty acids, cholesterol, and long-chain ceramides).5,26 The nucleated epidermis also contributes to the barrier through desmosomes, cytoskeletal components, tight junctions, and adherens junctions. Hence, the overall design of the skin, rather than a specific element, determines its efficacy as a protective barrier. The skin’s appendages, including sweat glands, pilosebaceous units, and hair follicles, emanate from the dermis or subcutaneous fat tissue, introducing significant discontinuities within this tight framework.27,28

Drugs administered to the skin’s surface access the skin through two pathways: the trans-appendageal and transepidermal routes, facilitated by passive diffusion. The skin’s appendages provide an alternative route for delivering medications into the skin, potentially making drug delivery through the stratum corneum (SC) less challenging.29 While this route was previously considered of minimal significance due to its relatively small area, current research on follicular penetration has shed light on the potential importance of hair follicle pathways in the skin penetration process and the reservoir for topically administered chemicals. Nanosuspensions are colloidal dispersions of nanosized drug particles in an aqueous vehicle. When applied to dermal surfaces, nanosuspensions offer several potential mechanisms for improved drug delivery:

1-Increased Surface Area: The reduced particle size in nanosuspensions provides a larger surface area for drug contact with the skin, facilitating enhanced absorption.

2-Improved Penetration: Nanoparticles can penetrate the stratum corneum (the outermost layer of the skin) more effectively than larger particles. This improved penetration may lead to increased bioavailability of the drug.

3-Targeting Specific Skin Layers: Nanosuspensions can be designed to target specific layers of the skin or even specific cells, allowing for more controlled and targeted drug delivery.

4-Facilitated Drug Solubility: Nanosuspensions can enhance the solubility of poorly water-soluble drugs, potentially leading to better absorption through the skin.

5-Interaction with Skin Appendages: Nanoparticles may interact with hair follicles, sweat glands, or other skin appendages, facilitating localized drug delivery.30,31 As illustrated in Figure 1. Nanosuspensions have found diverse applications in topical formulations, offering advantages such as improved bioavailability and enhanced drug penetration. While limitations exist, ongoing research and technological advancements continue to address and overcome these challenges, making nanosuspensions increasingly promising for topical drug delivery. Nanosuspensions in topical drug delivery aim to address challenges associated with drug solubility, penetration, stability, and controlled release. Various methods are employed to achieve nanosized particles, each offering specific advantages depending on the characteristics of the drug and the desired application.

Figure 1 Schematic representation of proposed mechanism of increased dermal penetration of drug nanosuspension. Created with BioRender.com.

Furthermore, several dermatological conditions, such as acne, alopecia, and various skin tumors, are closely associated with the sebaceous glands and hair follicles. A molecule can traverse the epidermis through one of two pathways: transcellularly, by passing through the corneocytes, or intercellularly, by moving through the lipid domains that separate the corneocytes.4,32 Although it is generally accepted that the intercellular route serves as the primary pathway for drug penetration, this route is significantly restricted by the formidable barrier created by the outermost SC layer.33,34.

The current investigation involved a literature review where articles were gathered through searches on Google Scholar, PubMed, and Scopus, utilizing keywords such as nanosuspension, topical application, dermal, and drug delivery system. The selection of libraries was based on specific inclusion and exclusion criteria. Inclusion criteria encompassed literature providing insights into the use of nanosuspension-based drug delivery systems for topical applications, published between the years 2000 and 2023. Exclusion criteria involved review papers, and publications without full-text availability.

Preparation Methods for Nanosuspension

In the pharmaceutical field, researchers have devised a variety of techniques for the formulation of nanosuspensions. These methods can be broadly categorized into three main classifications: bottom-up technology, top-down technology, and a hybrid approach that integrates elements from both.35 Furthermore, advanced research efforts have yielded successful development of various preparation strategies, including supercritical fluid technology, an emulsification-solvent evaporation approach, and a melt emulsification approach.19,31 As illustrated in Figure 2, specific methods for preparing topical nanosuspensions for topical application can involve individual approaches or a combination thereof, such as the “smart crystal” technique, which combines high-pressure homogenization (HPH) and wet milling. Additionally, nanosuspensions can be prepared using a combination of two methods: anti-solvent preparation and HPH.

Figure 2 Main methods of nanosuspension preparation for topical applications.

High-Pressure Homogenization Method

The cavitation process is executed through the high-pressure homogenization (HPH) method, where a solution is expelled from cavities or fissures and then applied to disperse drug crystals, relying on the application of substantial shear forces.36 Microfluidization and piston-gap homogenization represent two homogenization concepts frequently employed in conjunction with specific homogenizers that adhere to these principles.5,19

According to the jet-stream theory of microfluidization, the coarse suspension accelerates within the homogenizing chamber due to high-speed forces like collision, shear, and cavitation, resulting in a reduction in particle size. This process involves two types of chambers: “Z” and “Y”. In “Z”-type chambers, the suspension repeatedly changes direction, leading to particle collisions and shear forces. In “Y”-type chambers, the suspension flow is divided into two streams, colliding head-on.13,22,37

In the second type of homogenizer, referred to as piston gap homogenization, the coarse suspension rapidly passes through a very narrow gap. All these procedures employ pressures ranging from 350 MPa to 500 bar. Smaller particle nanosuspensions (NSs) can usually be produced by increasing the pressure and the number of cycles.26 It involves initially agitating a freshly prepared coarse suspension containing the active pharmaceutical ingredient (API) and a stabilizer for a specific duration. Subsequently, this mixture is passed through a narrow gap under high pressure, with various processing parameters influencing the particle size alteration, ultimately resulting in the formation of a nanosuspension.

Media Milling Nanocrystals

Pearl ball mills or high-shear media mills are employed for the production of nanosuspensions. The mill consists of a recirculation chamber, a milling chamber, and a milling shaft. The drug is then directed through the mill, which contains small grinding balls or pearls, within an aqueous solution.38,39 These balls move through the interior of the grinding jar, striking the sample on the opposite grinding jar wall as they rotate at a very high shear rate, while the temperature is carefully controlled. A substantial reduction in particle size is achieved through the combined effects of friction and impact.12,20,40 The milling medium or balls are crafted from materials such as strongly cross-linked polystyrene resin with excellent abrasion resistance, zirconium oxide, or aluminum oxide sintered in ceramic. A piece of equipment suitable for achieving a particle size below 0.1 μm is a planetary ball mill (PM100 and PM200; Retsch GmbH and Co., KG, Haan, Germany). Wet milling was utilized to produce a nanosuspension of Zn-Insulin with an average particle size of 150 nm.10,41 The initially prepared coarse suspension of API and stabilizer is recirculated through the grinding chamber until the desired particle size range is attained.

Smart Crystal Method

The smart crystal method focuses on a specific nanosuspension formulation designed for dermal applications. The description highlights findings from this formulation as an example, emphasizing that this approach is unique and not representative of other methods used in the study or field. In essence, the summary underscores the specificity of the smart crystal method in the context of nanosuspension formulations for dermal use. This method combines low-energy pearl milling and high-pressure homogenization, as exemplified in the creation of rutin nanocrystals. When compared to a 5% solution of a water-soluble rutin-glycoside derivative, a nanosuspension containing 5% rutin in the form of non-dissolved nanocrystals exhibited 500-fold greater antioxidant activity when applied to the skin of human volunteers. This increased activity can be attributed to the higher solubility of active rutin as a nanocrystal, leading to a greater concentration gradient between the dermal formulation and the skin.1,29,42 Consequently, this phenomenon indirectly enhances the drug’s absorption rate.

Rutin that has already permeated the skin is swiftly replaced by molecules from the rapidly dissolving nanocrystals. Furthermore, the original lipophilic rutin molecule is believed to penetrate the skin more effectively than the hydrophilic rutin-glycoside derivative due to its higher affinity for the target sites.43–46

Nanoedge Method

Nanoedge technology operates on the principle of combining precipitation and homogenization. In this method, the drug is initially dissolved in an organic solvent. Subsequently, this solution is blended with a miscible anti-solvent for precipitation. The drug undergoes precipitation due to its limited solubility in the water-solvent mixture. This precipitation process is accompanied by high-shear processing, achieved through a combination of rapid precipitation and high-pressure homogenization.

Factors Affecting the Stability and Efficacy of Nanosuspension Stabilizers

The primary role of a stabilizer is to ensure the thorough wetting of drug particles in order to prevent Ostwald’s ripening and the agglomeration of nanosuspensions, thereby promoting the physical stability of the formulation. This is achieved by serving as a steric or ionic hindrance.7,13,22 The type and quantity of stabilizer employed have a substantial impact on both the physical stability and in vivo behavior of the nanosuspension. Various stabilizers, including lecithins, povidones, cellulosics, polysorbates, and poloxamers, have been used in nanosuspension development thus far. In the quest for creating a nanosuspension suitable for parenteral administration and capable of withstanding autoclaving, lecithin has emerged as the preferred stabilizer.16,47

Organic Solvents

When emulsions or microemulsions are utilized as templates, organic solvents become necessary in the nanosuspension formulation. In such cases, it is advisable to opt for pharmaceutically acceptable, less hazardous, water-miscible solvents like methanol, ethanol, chloroform, and isopropanol. Partially water-miscible solvents such as ethyl acetate, ethyl formate, butyl lactate, triacetin, propylene carbonate, and benzyl alcohol are also preferred over conventional hazardous solvents like dichloromethane in the formulation process.31,48

Co-Surfactants

When developing nanosuspensions with the aid of microemulsions, the selection of a suitable co-surfactant becomes a critical consideration. This is because the choice of co-surfactants can significantly affect the internal phase uptake and drug loading within a specific microemulsion composition, ultimately impacting the phase behavior. Although literature references often mention bile salts and dipotassium glycyrrhizinate as potential co-surfactants, other solubilizers, such as transcutol, glycofurol, ethanol, and isopropanol, can be employed in the formulation of microemulsions without introducing any undue risks.19,28

Other Additives

Nanosuspensions can incorporate various additives, which encompass buffers, salts, polyols, osmotic agents, and cryoprotectants. These aforementioned additives fulfill multiple roles aimed at enhancing the stability and efficacy of the nanosuspension.

Buffers assume a crucial role in the maintenance of precise pH levels, while salts contribute to system stability by providing ionic strength. Polyols, on the other hand, act as stabilizers, preventing particle aggregation. Osmotic agents are tasked with regulating the solution’s osmolarity to ensure compatibility with cellular structures. Finally, cryoprotectants are employed to safeguard the nanosuspension during freezing and thawing procedures.48,49

Post-Production Processing

Post-production processing becomes essential in nanosuspensions when the drug candidate is highly susceptible to hydrolytic cleavage or chemical degradation. Additionally, processing may be warranted if even the most effective stabilizer fails to maintain the nanosuspension’s stability over an extended period, or if certain routes of administration pose limitations.6,17,40

Given these considerations, techniques such as lyophilization or spray drying can be employed to generate a dry powder comprising nanoscale drug particles. When opting for either of these unit operations, a judicious decision must be made, taking into account the drug’s characteristics and cost-effectiveness. In general, spray drying proves to be a more cost-effective and practical choice compared to lyophilization.24,30

Parameters Evaluated Reflecting Characteristics of Nanosuspension Color, Odor, and Taste

Prior to commencing the formulation process of oral dosage forms, it is imperative to account for particular considerations. Particle size, crystal structure, and subsequent alterations in particle dissolution can all potentially lead to flavor discrepancies, particularly in the case of active ingredients. Changes in taste, odor, and color may also serve as indicators of chemical instability.7,22

Particle Size and Its Distribution

The particle size distribution plays a significant role in determining the physiochemical characteristics of the formulation, encompassing factors such as saturation solubility, dissolution rate, and physical stability. To assess the particle size distribution, several methods are available, including photon correlation spectroscopy (PCS), laser diffraction (LD), and the Coulter Counter Multisizer.40,48,49

PCS boasts a measurement range spanning from 3 nm to 3 µm, while the LD method covers a range of 0.05 to 80 µm. It’s worth noting that the LD approach yields a relative size distribution, whereas the Coulter Counter Multisizer provides an accurate count of individual particles. Given that the smallest capillaries have diameters of 5–6 µm, it’s essential that particles intended for intravenous (IV) therapy are smaller than 5 µm, as larger particles could potentially cause capillary blockages and embolisms.17,50

Zeta Potential

The zeta potential serves as an indicator of suspension stability. In cases where stability relies solely on electrostatic repulsion, a zeta potential of ±30 mV is requisite for maintaining stability. However, when a combination of electrostatic and steric stabilization is employed, a zeta potential of ±20 mV would suffice.4,16,18,32

Crystal Morphology

Methods such as X-ray diffraction analysis in conjunction with either differential scanning calorimetry or differential thermal analysis can be employed to elucidate the polymorphic transformations induced by high-pressure homogenization in the crystal structure of the drug.7,33 As a result of the high-pressure homogenization process, nanosuspensions have the potential to undergo modifications in their crystalline structure, potentially transitioning into an amorphous state or adopting alternative polymorphic patterns.8,20,21

Solubility and Dissolution Rate

Nanosuspensions offer a significant advantage over other methods by simultaneously enhancing both dissolution rate and saturation solubility. Distinct physiological solutions must be employed to determine these two crucial parameters.30,35 Saturation solubility and dissolution rate assessments are valuable for predicting the in vitro behavior of the composition. The reduction in particle size leads to an increase in dissolution rate, resulting in elevated dissolution pressure.37,51

Density

A critical parameter to consider is the specific gravity or density of the formulation. A decrease in density often indicates the presence of entrapped air within the formulation’s structure, and its over time. To assess density accurately at a specific temperature, it is advisable to employ a well-mixed and uniform formulation and utilize precision hydrometers for these measurements.2,17,52

pH Value

To mitigate “pH drift” and the coating of electrode surfaces with suspended particles according to (Shrestha et al, 2014), it is essential to measure the pH of an aqueous formulation at a specific temperature, and this measurement should only be conducted once equilibrium has been achieved following settling. It is crucial not to introduce electrolytes into the external phase of the formulation to maintain pH stability.15,22

Droplet Size

The droplet size distribution of microemulsion vesicles and nanosuspension are both colloidal systems used in pharmaceutical and other industries for drug delivery and formulation, can be assessed using either the light scattering method or electron microscopy. For dynamic light scattering, a spectrophotometer is employed, which utilizes a neon laser with a wavelength of 632 nm.39,52

Viscosity

The viscosity of lipid-based formulations with different compositions can be assessed at various shear rates and temperatures using a Brookfield-type rotating viscometer. However, not all nanosuspensions are lipid-based. Nanosuspensions can be formulated using various types of stabilizers and carriers, including polymers, surfactants, and other non-lipid-based materials. Lipid-based nanosuspensions are just one type of formulation used to create stable and effective nanosized drug particles. For this measurement, it is necessary to immerse the samples in a thermal bath that maintains the sample chamber of the instrument at 37°C.16,23

Physical Stability

The primary role of the stabilizer is to ensure comprehensive coverage of the drug particles, thereby preventing Ostwald ripening and agglomeration in the nanosuspension and ultimately offering a physically stable formulation by serving as either a steric or ionic barrier1,51 Stabilizers such as cellulosics, poloxamers, polysorbates, lecithin, polyoleates, and povidones are frequently utilized in nanosuspensions. When developing parenteral nanosuspensions, lecithin may be a suitable choice.6,29

Biological Performance

Irrespective of the chosen route and method of administration, establishing an in vitro/in vivo correlation and closely monitoring the drug’s in vivo performance are fundamental components of certain drug delivery systems. However, they may not be as applicable or straightforward for intravenous formulations due to the rapid and direct entry of the drug into the systemic circulation, bypassing many of the factors that make IVIVC relevant for oral formulations. This holds especially true for intravenously administered drugs, given the significant implications for their in vivo behavior. The drug’s performance in vivo is heavily reliant on organ distribution, which, in turn, is contingent upon its surface characteristics, including surface hydrophobicity and interactions with plasma proteins. To address these considerations, nanosuspensions are utilized.10,18 It is well-established that the quality and quantity of protein absorbed following intravenous injection of nanoparticles is an interaction of nanoparticles with proteins in the bloodstream, play a pivotal role in determining their ultimate destination within the body. Consequently, it becomes essential to apply appropriate methodologies to evaluate surface characteristics and protein interactions in order to gain insights into in vivo behavior. Techniques such as hydrophobic interaction chromatography can be employed to measure surface hydrophobicity, and the quantitative and qualitative assessment of protein adsorption following the intravenous injection of drug nanosuspensions in animals can be conducted using methods like 2-D PAGE.4,17,52

Topical Applications of Nanosuspensions

Nanosuspensions have been widely studied in preparation of topical applications, either for ocular, pulmonary, or dermal uses, as summarized below:

Nanosuspension for Ocular Drug Delivery

Topical ocular medication delivery is the most widely adopted method for addressing both external and internal ocular conditions.53–55 The choice of approach depends on whether drugs are required to be retained at the cornea and/or conjunctiva (eg, for conditions such as conjunctivitis, blepharitis, or keratitis sicca) or whether they need to traverse these barriers to access the internal eye tissues (eg, for conditions like glaucoma or uveitis), based on the specific target sites for various ocular diseases (Table 1).

Table 1 Examples of Ocular Drugs Nanosuspension with Their Methods of Preparation

Despite the numerous biological processes and physical barriers within the eye, it is well-documented that the ocular bioavailability of administered drugs is low, at approximately 5%.60–69 This is due to the constant drainage of fluids, the blink reflex, and the activity of metabolic enzymes, all of which can rapidly degrade drug molecules. Consequently, after application, the drug remains in the precorneal region for only a brief duration. For drugs intended to reach the inner eye, they must traverse two primary barriers that envelop the eyeball: the cornea and the conjunctiva. The choice of a specific approach depends on the physicochemical properties of the drug, the desired release profile, and the safety considerations for ocular administration. It is essential to carefully evaluate the trade-offs between improved drug delivery and potential adverse effects to select the most appropriate strategy for a given therapeutic agent.66,70,71

Topical Pulmonary Applications of Nanosuspensions

Pulmonary medication delivery, both locally and systemically, provides a non-invasive option for lung treatment (Table 2). Inhalers and nebulizers produce aerosols that can be directly administered to the lungs in individuals.72 The local application of therapeutic drugs to the lungs is the predominant approach for managing various respiratory disorders. It offers the advantages of greater selectivity and higher local drug concentrations compared to other routes of administration.17,73

Table 2 Examples of Pulmonary Drugs Nanosuspension with Their Methods of Preparations

In contrast, the pulmonary route has gained increasing attention as a potential method for systemic drug delivery due to the extensive alveolar surface area, the delicate epithelial barrier, and the significant vascularization conducive to drug absorption.75–78 Furthermore, drugs administered via the pulmonary route bypass the first-pass metabolism of the gastrointestinal tract, enter the systemic circulation, and may eliminate barriers associated with patient compliance.5,19,79 However, the effectiveness of drug delivery through this route depends significantly on factors such as aerosol particle size, particle shape and geometry, surface adhesive properties, and the mechanism and rate of removal from the respiratory system.80–86

One critical feature of the drug formulation is the aerodynamic diameter of the aerosol, which characterizes its aerodynamic behavior, taking into account size, density, and shape. Optimizing this parameter is essential for effective pulmonary administration. It’s important to note that the success of nanosuspensions in pulmonary delivery depends on various factors, including the specific drug properties, patient characteristics, and the intended therapeutic outcomes. Each approach has its advantages and limitations, and the choice of strategy should be tailored to the unique requirements of the drug being delivered.16,87,88

Topical Dermal Applications of Nanosuspensions

Typically, drug nanocrystals are considered a safe and well-tolerated dosage form for various administration routes.17,22,89 Nanocrystalline formulations are more effective in oral drug delivery due to two key mechanisms: enhanced solubility and dissolution rates and increased bioadhesion to the intestinal wall. Consequently, taking a drug in the form of nanocrystals orally results in a large concentration gradient between the gastrointestinal tract and blood vessels, leading to increased absorption and higher bioavailability.90,91 In addition to marketed products, there is significant ongoing research focused on developing new formulations to enhance oral bioavailability using nanosuspension technology. In ocular administration, carrier-free nanocrystals consisting of 100% pure medication may offer advantages by reducing eye irritation, which, in turn, reduces tearing and drainage of the implanted dosage.5,36,90

Several researchers are currently exploring the use of anti-inflammatory medications in the form of nanocrystals for ocular applications. Drug nanocrystals can also be found in the aqueous phase of pharmaceutical skin preparations, such as anti-inflammatory creams or gels, as well as in cosmetic skin preparations, including sunscreen and anti-aging treatments.17,20,92

Dermal nanocrystals are available for use in cosmetic products, primarily when conventional formulation methods prove less effective. The use of medication nanocrystals results in an enhanced concentration gradient between the formulation and the skin. “Supersaturated” formulations, with higher saturation solubility, enhance medication absorption through the skin.7,13 Polymers with a positive charge can serve as stabilizing agents for drug nanocrystals, thereby increasing their stability. The stratum corneum, a layer of the skin, has a negative charge, which further enhances the attraction of drug particles to the skin.18,93

Nanocrystals present a relatively new and highly intriguing approach within the various methods aimed at improving cutaneous (skin) application. Despite the increasing availability of various nanosuspension products over the past decade, primarily designed for oral administration.43,93 Only a limited number of studies have explored skin permeability and the accumulation of medications in the form of nanosuspensions (Table 3). However, the few published findings have unequivocally demonstrated the potential benefits of this approach for enhancing the cutaneous bioavailability of active ingredients with low to medium solubility.48,51 In fact, nanocrystals not only exhibit improved saturation solubility and dissolution rates but also display increased adhesiveness to the skin, thereby enhancing cutaneous distribution.

Table 3 Examples of Nanosuspension Formulations for Topical Application and Their Preparation Methods

Interest in this technique for dermal application has grown since the introduction of the first skin-protective and anti-aging cosmetic products based on nanosuspensions containing poorly soluble antioxidants like rutin and hesperidin.4,6,44,101 The aglycone of hesperidin, known for its antioxidative and anti-inflammatory properties and considered a highly effective anti-aging compound, was initially developed. The method for manufacturing nanocrystals for oral, intravenous, or cutaneous use remains consistent, with the only difference lying in the choice of stabilizers.27,30,43

Therefore, four specific stabilizers suitable for cutaneous use, including Poloxamer 188, Inutec SP1, Tween 80, and Plantacare 2000, are employed to create nanosuspensions of hesperetin using high-pressure homogenization. It’s worth noting that nanosuspensions stabilized by Inutec and Plantac are stable and show no changes in mean diameter size, as anticipated from the zeta potential data.44,46 On the other hand, the slight size increases observed in nanosuspensions stabilized by Poloxamer and Tween are not believed to hinder their use in cutaneous formulations.

Resveratrol, recognized for its antioxidant properties, has been judiciously chosen as the preferred candidate for incorporation into nanocrystals intended for use in creams, lotions, and gel formulations within the realm of cutaneous cosmetics.45,60 The production of resveratrol nanosuspensions involves the application of a high-pressure homogenization technique. An essential aspect of this process revolves around the meticulous monitoring of how preservatives influence the physical stability of these nanosuspensions. This scrutiny is vital due to the pivotal role that preservation plays in the context of cutaneous preparations.2,102

Concurrently, lutein nanosuspensions are prepared through high-pressure homogenization to heighten their dissolution rate and saturation solubility. These two factors are instrumental in determining the extent of oral bioavailability and the potential of these compounds to penetrate the skin. Lutein is widely recognized within the cosmetic and nutraceutical industries for its antioxidant properties and its capacity to counter free radicals. Furthermore, it exhibits potential utility in pharmaceutical applications as a supplementary antioxidant.46,102

Comparatively, when lutein is employed in the form of nanocrystals, it manifests a notable improvement in drug saturation solubility in contrast to its coarser powder counterpart. This improvement not only augments its solubility but also facilitates more effective penetration through cellulose nitrate membranes. Additionally, empirical observations have unveiled the impermeability of pig ears, often utilized as a model for skin permeation studies. This observation lends credence to the hypothesis that lutein possesses the inherent capability to traverse the skin barrier and fulfill its role as an antioxidant in the cutaneous environment.32,51,103

The utilization of nanosuspension technology for topical pharmaceutical formulations marked a significant advancement with the introduction of diclofenac sodium solid in oil nanosuspension. This innovation addressed the challenge of delivering medicinal drugs with poor solubility. An example of this approach involved ibuprofen, a non-steroidal anti-inflammatory drug used in the treatment of acute and chronic arthritic conditions. Ibuprofen, due to its limited solubility, was considered for enhancing skin permeability through nanosuspension gel formulations.103,104

Topical application of ibuprofen offers advantages by minimizing adverse reactions, particularly gastrointestinal issues, which can result from oral administration, potentially harming the gastric mucosa and leading to ulceration. Research has demonstrated that the choice of solubilizer and the particle size of drug crystals play a significant role in improving skin permeability.17,44,101 These factors lead to the development of a supersaturated solution around the drug crystals, creating a substantial concentration gradient between the crystals and the skin surface. Consequently, the formulation of effective dermal formulations for poorly soluble substances must consider various factors, including drug crystal size, carrier surface properties, and drug-stabilizer interactions.14,28,104

To enhance the cutaneous targeting and photostability of tretinoin, a poorly water-soluble and unstable compound used in commercial creams and gels for treating acne vulgaris, nanosuspensions were produced using a straightforward precipitation approach.105,106 The permeation and deposition of drugs were studied through skin diffusion tests on newborn pigs, while UV light exposure was used to assess the photostability of tretinoin (TRA). Additionally, an oil-in-water (O/W) nanoemulsion was created and evaluated as a suitable comparator. Nanoemulsions have proven particularly valuable as carriers for cutaneous and transdermal delivery of hydrophobic substances in pharmaceutical, cosmetic, and chemical industries.8,89 The nanosuspension effectively localized the drug within pig skin throughout numerous transcutaneous studies, resulting in limited transdermal drug delivery (a factor contributing to systemic adverse effects). In contrast, the nanoemulsion significantly improved drug permeation.4,6,17,104

This investigation underscores the substantial potential of nanosuspensions in cutaneous drug delivery. It is noteworthy that nanosuspensions primarily consist of drug nanoparticles and minute amounts of safe and biocompatible surfactants, such as soy lecithin in this study. While there is limited toxicological data available at present, topically applied nanocrystals are not associated with known or anticipated adverse effects.39,107

Indeed, as proposed by several authors, it is noteworthy that each solid macro/microparticle applied to the skin undergoes a transformation into nanocrystals during its breakdown process, which is related to the concept of mechanical or physical breakdown, often associated with processes like milling or grinding. Importantly, there have been no documented reports of intolerance to this phenomenon thus far. As mentioned earlier, the authors of this study have provided additional support for the notion of improved drug delivery through the skin, emphasizing the establishment of an increased concentration gradient between the dermal formulation and the skin.11,41,43

Subsequent research has indicated that the enhanced dissolution rate of tretinoin nanocrystals can be attributed to their finely fragmented and uniformly dispersed nature. This characteristic promotes quicker dissolution due to the enlarged surface area and improved saturation solubility. Furthermore, in comparison to the control nanoemulsion, the utilization of tretinoin nanocrystals via topical administration yields the advantage of enhancing the drug’s photostability.105–108

Moreover, over the past two years, nanocrystal technology has been extended to include medium-soluble chemicals. This expansion signifies an important development, introducing a new mechanism by which nanocrystals can enhance cutaneous drug delivery. This mechanism involves the active participation of hair follicles, opening up a second pathway for improved drug delivery.18,22,107

These specialized shunts can aggregate nanocrystals of the appropriate size, approximately 700 nm, which function as a reservoir from which the medication can gradually diffuse into the neighboring cells, ensuring an extended release. The aim of augmenting the skin penetration of moderately soluble active substances, such as caffeine, has been a recent focus of various researchers. In pursuit of this objective, they developed a specific manufacturing method involving low-energy milling in dispersion media with low dielectric constants and the application of a chosen stabilizer. This approach was designed to counteract crystal growth and fiber formation, which are common outcomes of supersaturation and recrystallization effects observed in moderately soluble molecules.109–111

The innovative strategy they employed revolved around creating nanocrystals from active ingredients with moderate solubility. These nanocrystals were subsequently incorporated into a dermal formulation, serving as rapidly dissolving depots that enhanced saturation solubility and accumulated within hair follicles to further enhance skin penetration.16,110 For instance, caffeine nanocrystals were generated using a pear milling process in a mixture of ethanol and propylene glycol (3:7) with the addition of 2% carbopol. These nanocrystals exhibited a size range from 660 nm (ideal for hair follicle accumulation) to 250 nm (ideal for rapid dissolution).112,113

Challenges and Limitations

Addressing the limitations of nanosuspensions for topical application involves a combination of thoughtful formulation design, the selection of appropriate excipients, and the optimization of manufacturing processes. Formulation scientists should consider the specific requirements of the drug, the intended application, and the desired therapeutic outcomes when developing nanosuspension formulations for topical use.

Toxicity Hazards

Nanosuspension formulations are widely regarded as highly efficient excipients suitable for topical application in various contexts, including cutaneous, pulmonary, or ocular applications. Their effectiveness for these purposes can be attributed to several key advantages.

To begin, nanosuspensions exhibit remarkable physical stability. The reduced particle size of the drug in the formulation facilitates superior dispersion while preventing sedimentation or aggregation. This, in turn, ensures uniform distribution and consistent drug delivery, ultimately leading to enhanced therapeutic efficacy.

Additionally, nanosuspensions possess a notable surface area-to-volume ratio. This characteristic promotes improved drug dissolution and bioavailability, as the augmented surface area enables quicker and more efficient absorption into the target tissues or cells.

Furthermore, nanosuspensions exhibit a favorable toxicological profile. The excipients utilized in these formulations are generally recognized as safe and well-tolerated by the body. This reduces the likelihood of adverse effects or toxicity associated with the excipient itself.

In summary, nanosuspension formulations offer exceptional physical stability, enhanced drug delivery, and a low risk of toxicity. These attributes make them highly effective excipients for topical applications in cutaneous, pulmonary, or ocular treatments.24,44,105

Regulatory Considerations

In the realm of pharmaceutical development, the allocation of resources often hinges on the commercial context and the correlation between the developmental costs of a product intended for a particular market and its potential annual sales. Consequently, considerable innovation efforts have traditionally been channeled toward the oral and parenteral/intravenous routes. Nevertheless, there exists a noteworthy avenue for innovation in the application of drug nanocrystals for alternative routes such as cutaneous (topical), pulmonary (inhalation), and ophthalmic (eye) administration, offering opportunities for enhancing drug delivery.

In elucidating this point, it is crucial to acknowledge that the primary focus of innovations in drug delivery systems has been predominantly directed towards oral and parenteral routes. However, there has also been a growing interest in harnessing the potential of drug nanocrystals for alternative modes of administration, including cutaneous, pulmonary, and ophthalmic routes. Each of these routes presents distinct advantages and challenges in the context of drug delivery, and the integration of drug nanocrystals holds the promise of enhancing the effectiveness and safety of these administrations.

For instance, in the domain of cutaneous application, drug nanocrystals have the capacity to facilitate the penetration of drugs through the skin, ultimately enhancing their absorption and therapeutic outcomes. In pulmonary delivery, drug nanocrystals can significantly enhance the deposition of drugs in the lung, thus enabling targeted therapy for respiratory conditions. In the sphere of ophthalmic administration, nanocrystals offer the potential to augment drug permeability across ocular barriers, resulting in improved biodistribution and bioavailability.

Collectively, the integration of drug nanocrystals into these alternative routes of drug administration represents a promising avenue for optimizing drug delivery, diversifying treatment options, and ultimately improving patient outcomes.39,52

Future Perspectives and Research Directions

To date, numerous research teams have explored a variety of formulations using nanosuspension technology. However, only a limited number of these formulations have successfully reached the market, particularly for oral delivery. The underlying reasons for this situation extend beyond technical challenges, as the high market entry costs make it difficult to replace a well-established product with a nanosuspension. Additionally, established and proven administration methods are often preferred when introducing a novel chemical. In summary, nanosuspension technology provides a versatile framework for the development of safe and effective formulations for active compounds with poor solubility.112–114

In recent years, there has been a growing trend in the utilization of surface-modified nanosuspensions for the creation of tailored formulations. The use of drug nanocrystals holds promise for facilitating targeted drug delivery to specific diseased tissues, such as infected macrophages, tumors, and the brain, thus potentially enhancing pharmacological efficacy. Ongoing research is dedicated to exploring the application of nanosuspensions for the purpose of delivering nanoparticles to specific cells and enhancing their uptake within the cellular environment. Therefore, nanocrystals represent a viable approach for addressing challenges associated with the current dosage formulations.3,19,46,115

Conclusion

Nanosuspensions present a promising and economically viable strategy for addressing the challenges associated with delivering hydrophobic drugs, especially those characterized by limited solubility in both aqueous and organic solvents. These challenges predominantly pertain to enhancing drug absorption and bioavailability in the context of poorly water-soluble drugs. The latest nanosuspension manufacturing process can be established using wet milling, high pressure homogenization (HPH), smart crystal, and nanoedge methods. Furthermore, the integration of drug nanoparticles into water-free ointments and creams holds the potential to augment their saturation solubility, thus facilitating improved drug absorption through the skin. The ongoing advancements in mucosal formulations and topical administration are expected to maintain interest in nanosuspension drug delivery, characterized by simplified formulation techniques and a broad spectrum of potential applications.

Abbreviations

API, active pharmaceutical ingredient; DoE, Design of Experiments; GmbH, company with limited liability; HEC, Hydroxyethyl cellulose; HPH, high-pressure homogenization; HPMC, Hydroxypropyl Methylcellulose; IV, intravenous; LD, laser diffraction; MPa, megapascal; NSAIDs, Nonsteroidal Anti-Inflammatory Drugs; NSs, nanosuspensions; PCS, photon correlation spectroscopy; PS, particle size; PVA, polyvinyl alcohol; PVP, Polyvinylpyrrolidone; SC, stratum corneum; TPGS, tocopherol polyethylene glycol succinate; TRA, to assess the photostability of tretinoin; UV, Ultraviolet.

Acknowledgments

We would like to thank The Rector of Universitas Padjadjaran for the APC and Article Review Project. Also, we would like to thank The Libyan Ministry of Higher Education, and Elmergib University for a doctoral scholarship.

Funding

No funding was received.

Disclosure

The authors declare no conflicts of interest in this work.

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