Nanosuspension: A Novel Approach to Improve the Solubility, Bioavailability and Pharmacokinetics of Poorly Soluble Drugs
Arpita Tupe*, S.D. Mankar
Department of Quality Assurance Technique, Pravara Rural College of Pharmacy, Pravaranagar,
Tal: Rahta, Dist Ahmednagar, 413737, India.
*Corresponding Author E-mail: arpitatupe75@gmail.com
ABSTRACT:
Solubility is an essential factor for drug effectiveness, independent of the route of administration. Poorly water soluble drugs show major problems for drug formulation. Many conventional methods exist to address the issues of poor solubility and bioavailability, but they have many drawbacks. Nanotechnology is employed to address the issues related to these traditional methods for improving solubility and bioavailability. Pharmaceutical nanosuspension is a very finely colloid, biphasic, dispersed, solid drug particles in an aqueous vehicle, size below 1µm, without any matrix material, stabilised by surfactants and polymers, prepared by suitable methods for Drug Delivery applications, through various routes of administration such as oral, topical, parenteral, ocular and pulmonary routes. This article covers the advantages, disadvantages, properties, preparation of nanosuspension by bottom up technology, top down technology, melt emulsification, emulsification- solvent evaporation and supercritical fluid with their advantages and disadvantages, evaluation, and their drug delivery applications.
KEYWORDS: Solubility, Bioavailability, Nanotechnology, Nanosuspensions.
INTRODUCTION:
Poor solubility and poor permeability of the lead compounds are two major issues causing the low success in the creation of novel molecular entities as therapeutic formulations.1,2 More than 40% of the novel chemical entities created to date by drug discovery programmes are lipophilic or have low water solubility. Poorly water soluble medication development has always been a difficult problem for pharmaceutical researchers to solve.
To address this problem, all therapeutic molecules in biopharmaceutical categorization system (BCS) classes II and IV can be given a nanosized formulation to make them more soluble and achieve greater bioavailability.3 Nanosuspension is designed to enhance bioavailability and absorption, which may help to reduce the dosage of conventional oral dosage forms. Nanoparticles are typically polymeric colloidal carriers of pharmaceuticals, whereas nanosuspension technology maintains the drug in the necessary crystalline state with smaller particle size, resulting in a higher dissolving rate and hence improved accessibility.1 Nanosuspensions are colloidal dispersions of medication particles that are nanometer in size and are stabilised by surfactants. They may alternatively be defined as a biphasic system with pure drug particles suspended in an aqueous fluid with a diameter of less than 1µm.4 Controlling particle size, surface characteristics, and the release of pharmacologically active substances are the main objectives in creating nanosuspension as a drug delivery system in order to accomplish the drug's site-specific effect at the therapeutically ideal pace and dose regimen.5 These can be used to improve the solubility of medications that are insufficiently soluble in lipid and aqueous environments. Application methods for nanosuspensions include parenteral, oral, ophthalmic, and pulmonary routes. To expand their uses in site-specific medication delivery, work is now being done.6,7 In addition to addressing the issues of low solubility and bioavailability, nanosuspension also modifies the pharmacokinetics of the medication, enhancing therapeutic efficacy and safety.8
Advantages of Nanosuspension:2,6,7,9–13
1. Reduced tissue irritation whether administered subcutaneously or intramuscularly.
2. Increased drug saturation solubility and dissolution rate.
3. Physical stability throughout time.
4. The ability to achieve higher drug loading.
5. Greater bioavailability for inhalational and ocular medication delivery.
6. Nanosuspension can be utilised in tablets, gel, pellets, lotions, and capsules.
7. Offer passive targeting
8. Rapid onset, a lower fed/fasted ratio, and increased bioavailability are all benefits of oral administration of nanosuspensions.
9. Due to the drug's high dissolving rate and saturation solubility, it can improve in vivo performance.
10. Scalability for large-scale production and ease of manufacturing.
11. The potential for site-specific medication delivery by surface modification.
12. The crystalline structure and solubility of the particles may alter as a result of the nanosuspension technology's ability to enhance the amorphous percentage in the particles.
Disadvantages of Nanosuspension:
1) Sedimentation, compaction, and physical constancy can be problematic.
2) Inadequate dosage.
3) A uniform and precise dosage cannot be achieved.
4) It requires careful handling and shipment because it is bulky enough.
5) Suspension is required to provide uniform and precise dosing. 14
Properties of Nanosuspension:
Following are the properties of nanosuspensions
· Physical long term stability
· Internal structure of nanosuspension
· Adhesiveness
· Crystalline State and Particle Morphology
· Increase in Saturation Solubility and Dissolution Velocity of Drug
· Nano Suspension Provide Passive Targeting
1) Physical long term stability:
Ostwald ripening, which causes crystal development to generate microparticles in dispersed systems, causes physical instability. The discrepancy in the dissolution velocity/saturation solubility of small and big particles is what leads to Ostwald ripening. Ostwald ripening is completely absent in nanosuspensions since all of the particles are homogeneous in size and have same saturation solubility for drugs.
2) Internal structure of nanosuspension:
Internal structural changes in the drug particles are brought on by the high energy input during the disintegration process. The drug's crystalline state is changed to an amorphous state when it is subjected to high-pressure homogenization. The number of homogenization CYCLES, chemical makeup, and power density used by the homogenizer, together with the drug's hardness, all affect the state change.
3) Adhesiveness:
Comparing ultra-fine particles to coarse powders, there is a definite increase in adhesiveness. Small drug nanoparticles' ability to stick together can be used to enhance the oral administration of medications that aren't particularly soluble.
4) Crystalline State and Particle Morphology:
Understanding the polymorphism or morphological changes that a medication may experience when subjected to nanosizing requires consideration of both the particle morphology and the crystalline state. Due to high-pressure homogenization, nanosuspensions can transform from their original crystalline structure to one that is amorphous or has other polymorphism properties. By using differential scanning calorimetry in addition to X-ray diffraction analysis, it is possible to evaluate changes in the drug particles' solid state as well as the size of the amorphous portion. Scanning electron microscopy is chosen to provide a precise understanding of particle morphology.15
METHOD OF PREPARATION:
Currently, two methods are employed to prepare nanosuspensions: bottom-up technology and top-down technology.
Bottom up technology:
As the name implies, this method begins at the most fundamental level—the molecular level—and progresses to molecule association for the creation of tiny solid particles. This indicates that the solvent amount should be decreased in the innovative precipitation approach.16
a) Precipitation method:
The medicine is initially dissolved in a solvent, and after this solution has been combined with an antisolvent, surfactants are added to the mixture to make it miscible. When a drug solution is added quickly to an antisolvent, the drug becomes suddenly super-saturated and forms ultrafine crystalline or amorphous drug solids.9 Simple processes, simplicity of scaling up, and cost-effective production are benefits. The necessity to use surfactants to minimise crystal growth is one of the disadvantages. One or more solvents must be soluble in the drug.
Top down technology:
The disintegration approach is top down technology. The top down technologies, which are favoured over the precipitation approach, include media milling, high pressure homogenization, the emulsion diffusion method, and the supercritical fluid method.16
a) Milling techniques:
i) Media milling:
Liversidge (1992) was the first to devise and document this technique. By using this technique, high shear media mills are used to create the nanosuspensions.12 The milling chamber was loaded with milling medium, water, drug, and stabiliser and spun at a very high shear rate for at least 2 to 7 days at a regulated temperature.6 The impaction of the milling media with the drug causes the drug's microparticles to break down into nanoparticles, creating the high energy shear forces.
Advantages:
1. Simple Method
2. Low-cost milling procedure in terms of the actual milling.
Disadvantages:
· The product might get contaminated as a result of possible erosion from the grinding material.
· Potential microbial growth during protracted water phase milling.9
ii) Dry co-grinding:
Many nanosuspensions are being made using the dry milling process. Dry-cogrinding may be done quickly, affordably, and without the need of organic solvents. Because of an improvement in surface polarity and a change from a crystalline to an amorphous drug, co-grinding improves the physicochemical characteristics and dissolving of poorly water soluble medicines.17
Advantages:
1. Simple procedure; no need for an organic solvent.
2. Require little time for grinding.
Disadvantages:
Production of milling media residue.
b) High pressure homogenization:
This approach is applied to medications with limited solubility. In order to reduce the boiling point of the water to normal, the suspension is passed through a short region under high pressure (up to 1500 bar), which boosts the dynamic pressure and simultaneously lowers the static pressure (room temp)
i) Homogenization in water (Disso cubes):
The drug suspension is allowed to pass through a small aperture, which lowers the static pressure below the boiling water pressure, causing the water to boil and gas bubbles to develop.9 When the bubbles pop, the product particles in the outside section rush to the centre, forming colloids that reduce the particle size.
Advantages:
a) The deterioration of treated materials is not a result of it.
b) It applies to medications that have a difficult time dissolving in both aqueous and organic medium.
Disadvantages:
· Drug pre-processing, such as drug micronization, is necessary.
· The price of the dosage form is increased by the necessity of expensive tools.18
ii) Homogenization in Nano aqueous media (Nano pure)
For the thermolabile substance, it includes homogenization in water mixes or media without water. Because drug suspension is homogenised in non-aqueous fluids at 0°C, nano pure is also known as deep freezing.9
iii) Combined Precipitation and Homogenization (Nano Edge)
The medication is dissolved in an organic solvent, and to precipitate it, the solution is combined with a miscible anti-solvent. The medication has a poor solubility in the water-solvent combination and precipitates. High shear processing has been combined with precipitation. Precipitation and homogenization have the same fundamental concepts as Nanoedge. These methods are combined to produce smaller particle sizes and improved stability more quickly.
iv) Nanojet Technology
The term "opposite stream technology" also applies to nanojet technology. This method involves passing a stream of suspension that has been separated into two or more sections under high pressure so that they colloid together. As a result of the strong shear forces generated during the process, the particle size is reduced.
Advantages:
i) The use of specialised equipment is not required.
ii) By adjusting the emulsion droplet size, particle size may be readily regulated.
iii) Scale-up will be simple if formulation is correctly tuned.
Disadvantages:
i) This process cannot be used to create substances that are poorly soluble in both aqueous and organic environments.
ii) The method's use of potentially dangerous chemicals raises safety issues.
iii) The need for double ultrafiltration, which might make the purification of the drug nanosuspension expensive.
iv) A significant quantity of stabiliser or surfactant is needed.19
c) Melt emulsification method:
The substance is heated above the drug's melting point, homogenised, and dispersed in an aqueous solution of the stabiliser to create an emulsion. The sample container was covered with a heating tape that had a temperature control during the experiment, and the emulsion temperature was kept above the drug's melting point. Following that, the emulsion was progressively cooled to room temperature or placed in an ice bath.
Advantages:
In contrast to the solvent diffusion approach, the melt emulsification technology completely avoids organic solvents throughout the production process.
Disadvantages:
Formation of bigger particles and certain compliant objects compared to solvent evaporation.
d) Emulsification solvent evaporation technique:
In this method, a drug solution is prepared, and it is then emulsified in a liquid that isn't a solvent for the drug. The solvent evaporates, causing the medication to precipitate. High shear forces produced by a high-speed stirrer can be used to regulate crystal formation and particle aggregation.
e) Super Critical Fluid (Scf) Method:
Nanoparticles may be created from medication solutions using supercritical fluid technology. There are other techniques that have been tried, including the rapid expansion of supercritical solution (RESS), the supercritical anti-solvent process, and precipitation with compressed anti-solvent process (PCA). In the RESS, a nozzle is used to expand the drug solution in supercritical fluid, which causes the supercritical fluid to lose some of its solvent power and cause the drug to precipitate as tiny particles. The PCA technique involves atomizing the medication solution and injecting it into a container filled with pressurised CO2. As the solvent is eliminated, the solution becomes oversaturated and precipitates as tiny crystals as a result.9
f) Other methods:
1) Micro emulsions 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 surfactants.
Advantages:
1. The use of certain apparatus is not necessary.
2. Controlling the emulsion droplet's size makes it simple to manage particle size.
Disadvantage:
This method cannot be used to produce medications that are poorly soluble in both organic and aqueous environments.
2) Hydrosol method:
With the small exception that the drug solvent in this process is completely miscible with the drug anti-solvent, it is quite similar to the emulsification solvent evaporation strategy. High shear pressures are capable of overcoming difficulties such as ostwald ripening and crystal formation.9,20
EVALUATION OF NANOSUSPENSION:
In-vitro evaluations:
(i) Color, Odor, Taste:
In orally delivered formulations, these qualities are particularly crucial. Changes in particle size, crystal habit, and subsequent particle disintegration can all be linked to variations in taste, particularly of active ingredients. Chemical instability can also be indicated by changes in taste, smell, and colour.
(ii) Particle Size Distribution:
The physiochemical behaviour of the formulation, such as saturation solubility, dissolving velocity, physical stability, etc., is determined by the particle size distribution. Photon correlation spectroscopy (PCS), laser diffraction (LD), and the coulter counter multisizer may all be used to determine the particle size distribution. The PCS technique has a measurement range of 3nm to 3µm, whereas the LD method has a range of 0.05 to 80µm. The LD approach only provides a relative size distribution; in contrast, the coulter counter multisizer provides the precise number of particles. Given that the smallest capillaries are 5–6µm in diameter and that a bigger particle size might result in capillary obstruction and embolism, particles used for IV therapy should be less than 5 µm.
(iii) Zeta Potential:
The stability of the suspension is indicated by the zeta potential. A minimum zeta potential of 30mV is necessary for a stable suspension stabilised purely by electrostatic repulsion, but a zeta potential of 20 mV would be adequate in the event of a combination electrostatic and steric stabiliser.
(iv) Crystal Morphology:
Techniques like X-ray diffraction analysis combined with differential scanning calorimetry or differential thermal analysis can be used to describe the polymorphic changes brought on by high-pressure homogenization in the drug's crystalline structure. Due to high-pressure homogenization, nanosuspensions may alter in crystalline structure, perhaps becoming amorphous or taking on other polymorphic forms.
(v) Dissolution Velocity and Saturation Solubility :
In comparison to other methods, nanosuspensions have the important advantage of being able to increase both the dissolution velocity and saturation solubility. Different physiological solutions should be used to determine these two parameters. The evaluation of dissolution rate and saturation solubility aids in predicting how the formulation will behave in vitro. According to Böhm et al., when particle size was decreased to the nanoscale range, both the dissolving pressure and velocity increased. A reduction in size raises the dissolving pressure.
(vi) Density:
An essential parameter is the formulation's specific gravity or density. A reduction in density frequently signals the existence of trapped air inside the formulation's structure. Precision hydrometers make such measurements easier. Well-mixed, homogenous formulation should be used for measuring density at a certain temperature.
(vii) pH Value:
To reduce "pH drift" and electrode surface coating with suspended particles, the pH value of an aqueous formulation should be measured at a certain temperature and only when settling equilibrium has been attained. To stabilise the pH, electrolyte shouldn't be introduced to the formulation's exterior phase.
(viii) Droplet size:
Either light scattering method or electron microscopy may be used to determine the droplet size distribution of micro emulsion vesicles. Spectrophotometer for dynamic light scattering that makes use of a neon laser with a 632 nm wavelength.
(ix) Viscosity measurement:
Using a Brookfield type rotating viscometer, the viscosity of lipid-based formulations of various compositions may be evaluated at various shear rates and temperatures. The samples for the measurement must be submerged in a thermal bath that keeps the sample chamber of the instrument at 370şC.
(x) Drug content:
Mannitol is only marginally soluble in Methanol: THF (1:1) combination, thus it was centrifuged at 8000rpm for 10 minutes to determine the drug content of the nanosuspension formulation. Lyophilized powder (weighing equivalent to 5mg of drug) was used in this experiment. The absorbance was measured at 210nm after the supernatants were collected and diluted with a Methanol: THF (1:1) combination. The calibration curve was used to determine the drug content.
(xi) Stability study:
In order to assess the stability of the improved nanosuspension formulation, the change in particle size during storage at 2–8°C was monitored. Malvern Master size 2000 was used to monitor any changes in the nanosuspension formulation's particle size over time.
Surface hydrophilicity, adhesion characteristics, and interactions with body proteins can all be used to evaluate surface-modified nanosuspensions.
In-Vivo Biological Performance:
Regardless of the route and administration mechanism used, establishing an in-vitro/in-vivo correlation and monitoring the drug's in-vivo performance are crucial components of the study. Since the drug's in-vivo behaviour depends on the organ distribution, which in turn depends on its surface characteristics, such as surface hydrophobicity and interactions with plasma proteins, it is especially crucial in the case of intravenously administered Nanosuspensions. In fact, the crucial component for organ distribution is acknowledged to be the qualitative and quantitative content of the protein absorption pattern observed following the intravenous injection of nanoparticles. Therefore, it is necessary to examine surface features and protein interactions in order to gain an understanding of in vivo behaviour. Surface hydrophobicity may be measured using methods like hydrophobic interaction chromatography, and protein adsorption following intravenous injection of drug nanosuspensions in animals can be measured quantitatively and qualitatively using 2-D PAGE.8
APPLICATIONS OF NANOSUSPENSIONS:
1) Oral drug delivery:
The typical dosing route (oral medication delivery) has a variety of issues that result in poor solubility, insufficient absorption, and insufficient efficacy. Therefore, an oral nanosuspension has been developed to address the issue. Amphotericin B was made into a nanosuspension after oral absorption significantly improved as compared to the standard commercial formulation.
2) Parenteral drug delivery:
Poorly soluble non-injectable pharmaceuticals can be converted using nanosuspensions into a formulation suitable for intravenous delivery. Despite the importance of making nanosuspension for parenteral usage, recent advancements in this technology have shown its value as an injectable formulation. In female mice infected with Mycobacterium avium, clofazimine nanosuspension demonstrated superior efficacy than liposomal clofazimine in terms of both stability and effectiveness.
3) Ophthalmic drug delivery:
Drugs with limited solubility in lachrymal fluids may benefit greatly from nanosuspensions. Suspensions have several benefits, including the ability to stay in a cul-de-sac for a longer period of time—which is ideal for treating most ocular diseases—and avoiding the excessive tonicity that water-soluble medications can cause. Their real effectiveness is governed by the drug's inherent solubility in lachrymal fluids, which controls its release and ocular bioavailability. Ibuprofen is the greatest illustration of nanosuspension. Ibuprofen's anti-inflammatory efficacy increased when compared to the aqueous formulation.
4) Pulmonary drug delivery:
Nanosuspensions may be nebulized using mechanical or ultrasonic nebulizers for pulmonary administration. All aerosol droplets include medication nanoparticles because they contain a lot of tiny particles. Due to the tiny particle size, aqueous solutions of the medication are readily nebulized and administered via the pulmonary route.
5) Transdermal drug delivery:
The process of "nanonization" reduces the size of the drug particle. The primary drawbacks of the transdermal route are caused by the sluggish penetration of many medicines over the skin barrier. These methods to penetrate the epidermal barrier include topical formulations with penetration enhancers.
6) Targeted drug delivery:
Targeting their surface characteristics and modifying the stabilisers' behaviour may both be done using nano suspension. Drugs that are poorly soluble can be administered to the brain with nanosuspensions while experiencing fewer negative effects. A effective example involves using surface-modified polysobutyl cyanoacrylate nanoparticles to target the peptide Dalargin to the brain.
7) Topical drug delivery:
Creams and water-free ointments can include drug nanoparticles. Medication diffusion into the skin is improved by the nanocrystalline forms' higher saturation solubility of the drug in the topical dose form.
8) Bioavailability enhancement:
Nanosuspensions address the twin issues of poor solubility and poor permeability across the membrane in order to address the issue of poor bioavailability. When compared to the dissolution from a coarse powder (15% in 20 min), the Lyophilized Nanosuspensions powder's rapid solubility (90% in 20 min) and consequently bioavailability dramatically increased the therapeutic impact. A nanosuspension formulation was used to increase the bioavailability of the hepatoprotective drug oleanolic acid, which is poorly soluble. Significantly improved treatment results suggested greater bioavailability.
9) Mucoadhesion of nanoparticles:
Orally administered drug nanoparticles from a nanosuspension quickly contact the mucosal surface after diffusing into a liquid medium. The "bioadhesion" adhesion process immobilises the particles at the gut surface. From this point on, the concentrated suspension serves as a particle reservoir and an adsorption process occurs quickly. Prior to particle absorption, the particles initially make direct contact with the intestinal cells through a bio adhesive phase. The Nano suspensions' adhesiveness not only aids in enhancing bioavailability but also enhances targeting of parasites that are still present in the GIT.2,15,21
CONCLUSION:
Drugs that are poorly soluble in organic or aqueous media or that are lipophilic and insoluble in both can be effectively treated using the nanosuspensions method. For the fabrication of nanosuspensions, large-scale production techniques such media milling or high pressure homogenization have been used. The properties, such as enhanced bio-adhesivity, higher saturation solubility, enhanced dissolving velocity, adaptability in surface modification, and simplicity in post-production processing, have expanded the applications of nanosuspensions for multiple routes of administration. Nanosuspensions can be administered in a variety of ways, including orally, topically, parenterally, and pulmonaryly. As a result, nanosuspension technology has the potential to significantly help patients and expand the field of pharmaceutical research.
FUTURE SCOPE:
The administration of hydrophobic pharmaceuticals, particularly those that are poorly soluble in aqueous and organic media, can lead to challenges with drug delivery, including low bioavailability. Nanosuspension technology offers an innovative and distinctive method to address these issues. Large-scale manufacture of Nanosuspensions has been successfully carried out using industrial techniques such media milling and high-pressure homogenization. Tablets, capsules, and pellets are some examples of conventional dosage forms that may be coupled with nanosuspension technology, as well as parenteral products. As oral formulations and non-oral administrations advance in the future, nanosuspensions will continue to be of interest in order to benefit from their drug delivery, straightforward production technologies, and range of uses. According to the data provided, nanosuspensions can be seen as the formulation technologies' resurrection in the years to come.
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Received on 18.04.2023 Modified on 02.06.2023
Accepted on 22.07.2023 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2023; 13(3):194-200.
DOI: 10.52711/2231-5713.2023.00035