INTRODUCTION:

Nanosuspensions are defined as colloidal dispersions of substances with particle size below 1 μm and poorly soluble drugs as the dispersed phase and surfactants or polymers as stabilizers. Unlike solid lipid nanoparticles and polymeric systems, they do not contain any matrix material. These systems improve the ability to dissolve and the rate of dissolution of hydrophobic drugs that are either insoluble in organic solvents or water at physiological ph. Nanosuspensions can be administered in several oral and parenterally active drug delivery systems including oral, ophthalmic, and inhalation¹^-².

Some of the techniques include wet milling, high pressure homogenization, melt emulsification solvent evaporation and supercritical fluid technique. Nanosuspensions afford site-specific delivery; incorporated in classified formulations such as mucoadhesive hydrogels and ocular system. Other mean nanotechnology has improved the dissolution rates as well as the absorption of drugs in the bodies.³^,^4,5.

Badly soluble drugs are a concern to pharma and the new kid on the block is nanosuspensions. The co-spray granulation technique is advocated as a potential approach to preparing these drugs. Being capable of enhancing bioavailability and solubility, nanosuspensions are in fact an enhancement to the present method of formulating drugs.^6,7.

Definition:

Formulations for drugs delivered through several routes (oral, topical, IV, etc.) contain small particles of solid active substances in the aqueous carrier with the stabilising or surfactant agents. These particles, which are generally below one micron (1000nm) and ranging from 10 to 1000nm enhance dissolving rate and bioavailability. The desirable size of the particles is between 200 and 600nm due to improved dissolution velocity resulting from increased surface area. Particles less than 10 micron diameter have high solubility and dissolution and there is strong evidence to believe that these nanosuspensions may benefit from vapor pressure effects that increase saturation solubility further enhancing the dissolution rate.^8,9.

Differentiating Nanosuspension:

Nanosuspensions proved themselves to be an exceptional innovation about the traditional methods of drug delivery systems inclusive of solid lipids, nanoparticles, and polymeric nanoparticles. They are a specific type of controlled/drug delivery system with solid submicron particles of the active compound dispersed in an aqueous phase. These particles are perfectly balanced by Surfactants thus form a stable colloidal dispersion of the solid particles and the liquid which is devoid of any matrix materials. This unique assists nanosuspensions to elude some of the drawbacks connected to other nanoparticle-based drug delivery systems^10–13.

Arise In Need Due to Poor Solubility:

The focal shift of nanosuspensions to becoming one of the most important pharmaceutical advancements stems from the existing problem of poor solubility affecting many newly developed drugs already become a known issue. A considerable portion of these medications have the properties of low solubility both in water and in organic solvents. Conventional drug. The problem of poor weight control is a natural feature, and formulation techniques are not always able to provide sufficient solutions to avoid a decrease in this parameter solubility and effectiveness of these drugs. This growing need for a solution to boost the bioavailability of the active pharmaceutical ingredient to patients dictates the development and use of appropriate device technology. Because many of today’s molecules are poorly soluble, the advancement and utilization of nanosuspensions have been advanced alternative^14,15.

Explicating The Significance of Nanosuspension:

1. Improved Drug Solubility:

The foremost purpose of nanosuspensions is the ability to meet the problem area of low solubility by decreasing the particle size of the drug to a lower particle size of sub-micron. This reduction significantly increases the external surface area of the drug particles increasing the amount of the drug dissolving in water and other organic solvents environments.

2. Elevated Bioavailability:

Hence, due to the solubility enhancement factor, nanosuspensions have a core responsibility of enhancing the drug's bioavailability. The particles with sizes below a micron dissolve faster; therefore, this change leads to a greater concentration difference between the site where the drug is administered and the body’s general circulation, then which enhances its rate of being absorbed by the body and hence is more effective^16,17.

3. Versatility in Pharmacotherapy:

Presumably, one of the most attractive features of nanosuspensions is versatility. They can encapsulate any type of a drug, in most cases regardless of the solubility of the drug substance. Due to these features, nanosuspensions can be used for the delivery of different drugs in pharmaceutics.

4. Ease of Formulation:

It can be understood that compared to other types of suspensions, nanosuspensions have a relatively simple formulation procedure relative to other sophisticated nanocarrier drug delivery systems based on nanoparticles. This simplicity streamlines use in manufacturing integrated products and is incorporated into many different pharmaceutical products.

5. Capacity For Personalized Therapies:

Being true colloidal systems, nanosuspensions present a reasonably less complicated technique of preparation relative to some other sophisticated categories of nanoparticles for drug delivery. This simplicity streamlines the manufacture of these products and helps to incorporate them into different dosage forms in the manufacture of pharmaceuticals^18,19.

Nanosuspensions are a notable advance in the field of pharmaceutical sciences as gives a solution to the unrelenting problem of low solubility of drug molecules that remain insoluble even in water. Because they are formulated differently and the roles they play, they provide an encouraging strategy. To increase the solubility and the therapeutic effect of many different drugs and therefore promote the effectiveness of patient outcomes.

Cause of Improving Bioavailability

According To BCS Class-II Medications:

1. Difficulties in Oral Bioavailability:

Pharmacokinetic imbalances of process-impacted medications that belong to BCS Class-II drugs show a typical problem of low oral bioavailability. This mainly originates from the problem of poor water solubility of these drugs, which adversely affects Assimilation and utilization within the body is another factor since they can be excellently absorbed and utilized by the body²⁰.

2. Discovering the Novel Techniques:

Some of the concerns that are related to the bioavailability that is gotten from BCS Class-II drugs. This has led to a search for new forms for overcoming the challenge as demonstrated by the following strategies. Nanosuspensions emerge as a potential solution because they may hold positive trends regarding the solubility of drug substances and, consequently, their commencement bioavailability²¹.

Challenges With Poor Solubility:

1. Prevalence of Solubility Issues:

More than half the drugs present solubility issues and this when taken to the immense directory of drugs means that solubility issues are a widespread problem and serious challenges for their proper development and administration. Within these, BCS Class-II medications. It is also worth noting that most of the identified compounds | are distinctively characterized by their very poor solubility in both organic and aqueous solvents²².

2. Complexity of Class II Medications:

Class II drugs, as include low solubility and high permeability, that is, the reagents that dissolve in the test substance only at a slow rate in the gastrointestinal tract. This reduces the amount that can be taken in and thus their bioavailability becomes affected.

3. Limitations of Conventional Approaches:

It is challenging to explain how traditional pharmaceutical techniques fail to solve contemporary multifaceted problems using the principles of reductionism and linearity problems associated with the solubility of BCS Class-II medications from the existing information. The formulation strategies include Solid emulsions, cyclodextrin inclusion compounds, or solubilizers in aqueous solutions with organic solvents sometimes fail to enhance the solubility and consequently the bioavailability of these drugs to the desired extent.

Nanosuspensions as a Solution:

1. Tailored Approach for Class II Medications:

Nanosuspensions thus present a general concept of format that is geared towards a specific use of the solubility issues more so in the case of BCS Class-II medications. By reducing drug the solid particle size down to the nanoscale, such suspensions make sense as a way to enhance solubility and subsequently enhance bioavailability.^23,24

2. Versatility and Effectiveness:

They are equally applicable for various medications as has been demonstrated in nanosuspensions regardless of the solubility problems that some may or may not encounter. They also improve the solubility of drugs that present challenges meaning it widens the prospects for solving problems better delivery system that prepares the way for the synthesized drugs’ successful therapeutic action²⁵^.

Thus, the widely reported problem of poor solubility of drugs, especially those belonging to BCS Class-II, requires new strategies like nanosuspensions. They also provide a specifically tailored method to improve the drug dissolution rates to tackle solubility issues, and subsequently enhance the BI of these drugs, which in turn promotes more effective therapeutic outcomes^26,27.

Method of Preparation of Nanosuspensions

Top-Down, Bottom-Up Methods and Combined Technologies:

1. Top-Down Approach:

This method involves scaling down particle size from macro size to the nanosized dimensions. Examples of this kind of technique include high-pressure homogenization and media milling. Here, it starts with bigger particles or moieties they are then fragmented into smaller particles, ultimately achieving nanosuspensions^28,29.

2. Bottom-Up Approach:

On the other hand, the bottom-up method is formed by joining nanoscale particles at atomic or molecular level components. Techniques like precipitation, emulsification- solvent evaporation, supercritical fluid, and other processes are examples of a bottom-up approach as shown in Figure 1. In these methods, nanoparticles are developed layer by layer from individual atoms/ molecules or existing clusters, atoms, compounds, or little particles and deposit in mass by accumulating into something bigger³⁰.

3. Combined Technologies:

There is, however, evidence in some works about the fact that the best strategy for particle preparation about size and stability is to employ a mix of both top–down and bottom–up procedures. Thus, it asserts the use of NANOEDGE™, H 69, CT (combination technology), H 96, and H 42 technology to achieve a good result of both bottom-up and top-down technology for small particle size e.g. preparation of atorvastatin nanoparticles via anti-solvent precipitation after probe sonication. For the birth of such nuclei, a few distinct nuclei with the given size are generated, preventing the formation of nuclei with a larger size when these two methods are applied jointly. However, using these methods together to achieve a small polymeric dispersity index (PDI), additionally, the range of the particle size is within the range that minimizes the growth of particles³¹.

Figure 1: Different Bottom-up Techniques for Preparation of Nanosuspension

Various Production Methods:

1. High-Pressure Homogenization:

This technique employs high pressure in that it compels drug particles by small openings, which limits their pore size. Besides, it is possible to maintain scalability and Productivity since the process can produce cheaply stable nanosuspensions. Nevertheless, it might take several cycles to achieve the desired degree of PSD as well²⁹.

2. Media Milling:

This method applies forces on the drug using milling media for high-energy forces to cause communication particles into smaller sizes. Although it is efficient in the sense that it creates particles of small sizes, it takes time and does lead to some of the particles being bigger than the nanoscale which is the desired scale.

3. Precipitation:

Precipitation entails causing sudden S/S of the drug by adding a solution by an antisolvent which in turn results in particle formation. It is quite a simple method; however, depending on the ideas presented, it may be somewhat challenging to implement coalescing agents and/or surfactants to slow the growth of particles and affect its stability^32,33.

4. Emulsification-Solvent Evaporation:

The method entails dissolving the drug in a solvent to form: Solvent was added to the weighted quantity of the drug The calculated quantity of solvent was added into the weighed quantity of the drug micro-emulsion method, stabilization of the produced nanoparticles after the solvent had been evaporated. It's advantageous for avoiding organic solvents but tends to yield larger particle sizes than the other techniques.

5. Supercritical Fluid Processes:

This technique makes use of supercritical fluids such as the carbon dioxide optimization of particle size of the drug to the sub-micrometer range. It is quite useful in the treatment process but it has some constraints; concerning the solubility of drugs and using high pressure on the samples^34,35.

6. Nano-edge Method:

Nano-edge 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 homogenization³⁶.

7. Nano pure:

It involves homogenization in water mixtures or water-free media and is prepared for the thermolabile compound. Nano pure is also called deep freezing because homogenization of drug suspension is carried out in non-aqueous media at 0³⁷.

Other Production Methods:

1. Microemulsions as templates:

This process creates an emulsion by mixing an organic solvent or mixture of solvents with the product that has been dispersed in an aqueous phase with the right surfactants³⁸.

Advantages:

· The use of certain apparatus is not necessary.

· Controlling the emulsion droplet's size makes it simple to manage particle size.

Disadvantages:

· This method is not suitable in preparing poorly soluble or insoluble active pharmaceutical ingredients in both organic and aqueous solvents.

2. Hydrosol method:

The only difference from this emulsification solvent evaporation strategy is the small minor difference that the drug solvent in this process is miscible with the drug anti-solvent. High shear pressures cannot cavitate and will be able to address challenges such as Ostwald ripening as well as the formation of crystals³⁸.

Benefits and Drawbacks of Techniques:

1. Advantages:

· Particle Size Control:

Depending on the technique used all the techniques present different levels of control over the particle size that is produced by tailored nanosuspensions.

· Stability and Scalability:

Some of the methods give stable nanosuspensions that can be scaled up production.

· Ease of Production:

Some of them are more direct and easier to recognize in their application.

2. Limitations:

Particle Size Distribution:

Here the techniques might produce a wider range of particle size classes affecting uniformity.

· Production Time:

Some of the methods may take a lot of time resulting in reduced productivity and effectiveness scalability.

· Stability Challenges:

In some cases, it will need extra stabilizers or surfactants to maintain nanosuspension stability^39,40.

The decision of how to manufacture nanosuspensions has the most influence on particle size and stability. The five forces that can shape Walmart’s competitive advantage include cost, availability of resources, customer demand, global relations, and Product development. All the technique mentioned above has their strengths and weaknesses, thus, the choice of the technique depends on the unique aspect of the research project depending on the type of the drug the almost unlimited process parameters concerning the particle characteristics and the intended application allow for an individual case consideration^40,41.

Recent Patents in Nanosuspension:

Over the past decades, nanosuspensions have been studied for their highly effective applications in drug delivery systems and this research work has found that the nanosuspensions have the potential to improve the efficacy of drug molecules⁴². Products based on nanosuspension are many on the market today with few being under trial for clinical use. The commercial use of nanosuspension-based formulation for oral route is vast already and products in other routes are near future market. Of all the techniques available, the wet milling technique is the only one that has been deployed for the commercial production of nanosuspension. The nanosuspension-based patents have the wider possibility that they would reach the market much faster than the other nanotechnology-based formulations⁴³. This review includes aspects of techniques of preparation, route of administration, and commercialization of nanosuspension with emphasis on the newly granted patents⁴⁴. Recently, more than 100 patents have been published on Nanosuspension⁴⁵.

This patent review is helpful to improve the understanding of controlled drug delivery and its applications. Patent number WO2016081593 talks of a pharmaceutical nanosuspension where the therapeutically active moiety is the active nutraceutical* ingredient capable of having poor solubility. These patents suggest that at least one alginate moiety was chosen ñ which is either sodium alginate or potassium alginate for preparing the nanosuspension.

Another example of a US patent is 20160317534 which is an example of the nanosuspension of a freeze-dried (lyophilized) drug. The stability of this freeze-dried drug nanosuspension for long-term storage was considered adequate. The method that pertains to the subject of the present invention is described in the patent WO2016135753. Such nanosuspension comprises the water-soluble active therapeutically effective ingredient or its salt in combination,

with a wetting agent and the non-aqueous solvent system. This non-aqueous nanosuspension was then transferred to topical nanosuspension⁴⁶.

Further information on the subject can be obtained from the Chinese patent number 105708844. Designed a new method of preparing ophthalmic nanosuspension. In this method, tobramycin and dexamethasone were used as active medicaments. The above-stated process of such nanosuspension is developed. It was also established that the work described herein is generalizable, efficient, reliable, and easy to apply.

Another Chinese patent 105315249 is associated with the successes and failures of the nanosuspension method using the simvastatin drug candidate. The researchers noted the steps followed that the above-mentioned method improved the efficiency of drug delivery system. Another similar Chinese patent 105534947 explains the method of manufacturing suitable for preparing the nanosuspension capsule of celecoxib which was transformed into solidified freeze-dried powder.⁴⁷

Patent and clinical aspects of HNMs:

Patents: Substantial patents have been filed on herbal-based nanoparticles with various biological activities. Since the last decade, a rapid increase in patent approval in herbal nanomedicine has been noted, which claims a significant increase in the solubility, bioavailability, sustainability, and targeted delivery of phytomedicine. Most of the patents were based on curcumin and relative nanoformulations⁴⁸.

Currently marketed pharmaceutical Nano suspension products⁸³ are shown in Table 1.

DISCUSSION:

Nanosuspensions have tremendous potential in overcoming the major challenge of poor drug solubility, particularly in BCS Class II drugs, increasing their bioavailability and thus offering better targeted pharmaceutical care. To this end, high-pressure homogenization, media milling, dry-co-grinding, emulsification, and solvent evaporation have become preferred preparation methods, but they have their advantages and disadvantages. High-pressure homogenization works industrially fast and with high efficiency but needs several cycles and preparation with a pre-suspension. In media milling, the particle size distribution is successfully reduced but the process needs proper control to minimize the variations. Other methods such as dry-co-grinding, emulsification, and solvent evaporation offer green or large-scale approaches but present problems such as the formation of residues, unevenness, or use of solvents respectively. The technique to be used is determined by the properties of the drug, therapeutic objective, and the environment surrounding the drug in conjunction with the nanosuspension which underscores the requirement for appropriate innovations to fully unlock the drug delivery system possibility of nanosuspensions.

CONCLUSION:

The detailed coverage of nanosuspensions along with their preparation methods also solves the tasks created by low solubility but at the same time presenting opportunities to alter the future of pharmaceutical formulations. This research lays the foundation for other developments and uses, thus advancing the field and its possibilities, nanosuspensions into being one of the most critical entities in contemporary drug delivery systems.

ACKNOWLEDGMENT:

The authors gratefully acknowledge their gratitude to The Principal, Yash Institute of Pharmacy, Dr. Babasaheb Ambedkar Marathwada University, Chh. Sambhajinagar (Aurangabad) for providing ICT facility.

AUTHOR CONTRIBUTIONS:

Conceptualization: Krishna Chopde

Literature Review and Data Synchronization: Nilay Shinde

Original draft preparation: Krishna Chopde, Amruta Jadhav

Review and Editing: Dr. Vandana Patil

All authors have read and agreed to the published version of the manuscript.

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Received on 20.10.2024 Revised on 13.01.2025

Accepted on 17.03.2025 Published on 18.04.2025

Available online from April 22, 2025

Asian J. Res. Pharm. Sci. 2025; 15(2):207-214.

DOI: 10.52711/2231-5659.2025.00032

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Trade/Company	Drug	Dosage Form /Route of Administration	Nanosuspension Method	Indication
Abraxane®/Abraxia Biosciences	Paclitaxel	Freeze-dried powder for injection/ Parenteral	nab™	Metastatic breast cancer
Cesamet®/Lilly	Nabilone	Capsule/Oral	Coprecipitation	Antiemetic
Emend®/Merck	Aprepiant	Capsule/Oral	Nanocrystal®Elan Nanosystems	Antiemetic
Giris-PEG®/Novartis	Griseofulvin	Tablet/Oral	Coprecipitation	Antifungal
Invega Sustenna®/ Johnson and Johnson	Palperidone palmitate	Liquid nanosuspension/ Parenteral	High-pressure homogenization	Schizophrenia
Megace ES®/Par Pharmaceutical Companies	Megestrol-acetate	Liquid nanosuspension/Oral	Nanocrystal®Elan Nanosystems, Media milling	Anorexic
Rapammune®/Wyeth	Sirolimus	Tablet/Oral	Nanocrystal®Elan Nanosystems	Immunosuppressant
Tricor®/Abbott	Fenofibrate	Tablet/Oral	Nanocrystal®Elan Nanosystems	Hypercholesterolemia
Triglide®/First Horizon Pharma	Sirolimus	Tablet/Oral	IDD-P® Skyepharma	Hypercholesterolemia
Avinza®/King Pharmaceuticals	Morphine sulphate	Tablet/Oral	Nanocrystal® ElanNanosystems	Psychostimulant
Ritalin®/Novartis	Methyl Phenidate HCl	Capsules/Oral		Muscle Relaxant
Zanaflex™/Acorda	Tizanidine HCl	Tablet/Oral		Muscle Relaxant