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Nanosuspensions as particulate drug delivery systems

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Jignyasha A. Raval

Jignyasha A. Raval

Today, in many cases the newly developed drugs are poorly soluble in both aqueous and non aqueous media. A basic problem of poorly soluble drugs is often an insufficient bioavailability.

To solve these problems formulation as nanosuspensions is an attractive and promising alternative.One of the major advantages of this technology is its general applicability to most drugs and its ease. Here, the characterization, various properties and application of nanosuspension technology are discussed.

Introduction

Solubility problems of many newly developed high-potential drugs are a severe obstacle in formulation development, especially when they show poor solubility simultaneously in aqueous and organic media

[1]

. This leads, in many cases, to a poor and/or varying bioavailability after oral administration which often, in many cases not replaced by parenteral administration. Poorly soluble components in solution as IV injection are not possible. Parenteral administration as a micronized product (e.g. I.M. or I.P.) does not lead necessarily to sufficiently high drug levels because the solute volume at the injection site is too low.
Various attempts to increase the saturation solubility, and thus solving the problem, have been tried. These include solubility enhancement by using solubilization (e.g. mixed micelles for i.v. injection), non-specific or dispersed specific complexation (e.g. addition of polyethylene glycol (PEG) or use of cyclodextrins) and solvent mixtures (e.g. ethanol–water, up to 20% ethanol is possible). But the limited success of these attempts is predictable by the very low number of products in the market which are based on these principles.
For a long duration of time micronization of poorly soluble drugs by colloid mills or jet mills was preferred. The overall particle size distribution ranges from 0.1 µm to approximately 25 µm, only negligible amount being below 1 µm in the nanometer range
[2].

Micronization increases the dissolution velocity of the drug due to the increase in surface area but does not change the saturation solubility.

Further the development was, transformation of the micronized drug powder (i.e. drug microparticles) to drug nanoparticles

[3,4].

In the eighties, drug nanoparticles were produced by Sucker and co-workers
[5–7]
using a precipitation technique. Precipitation was performed by dissolving the drug in a solvent and adding this solvent to a non-solvent. The most important confront of this technique is that during the precipitation procedure the growing of the drug crystals needs to be limited by surfactant addition to avoid formation of microparticles. The fundamentals limiting the applicability of the precipitation technique are the need of the drug to be soluble at least in one solvent and that this solvent needs to be miscible with a non-solvent. These prerequisites exclude the processing of drugs which are simultaneously poorly soluble in aqueous and in non-aqueous media.

Use of a pearl mill leads to the product NanoCrystals® (company NanoSystems, Liversidge et al.
[4]
) and the use of a high pressure homogeniser to nanosuspensions: DissoCubes® (Skye Pharma PLL, UK, Müller et al.
[3]
). To produce NanoCrystals®, the drug powder is dispersed in a surfactant solution and the obtained suspension undergoes a pearl milling process for hours up to several days. Special features such as increased saturation solubility and dissolution velocity, and special applications, for example, mucoadhesive nanosuspensions for oral delivery and surface-modified drug nanoparticles for site-specific delivery to the brain are talked about.

Characterization of nanosuspensions

When initiating any formulation design, some of the basic characteristic parameters of the dosage form are important and need to be known. Similarly there are many such characteristic parameters of a nanosuspension that are essential.

Essential characterization parameters for nanosuspensions are:

[8]

(1) Size and size distribution

(2) Particle charge (zeta potential)

(3) Crystalline status

(4) Dissolution velocity and saturation solubility.

For surface-modified nanosuspensions a number of additional parameters have to be investigated to obtain a complete picture, especially with relevance for the in-vivo behavior:

(5) Adhesion properties (in case of mucoadhesive particles)

(6) Surface hydrophilicity / hydrophobicity

(7) Interaction with body proteins.

 

The polydispersity index (i.e. mean size and width of distribution) is determined by photon correlation spectroscopy

[9].
The photon correlation spectroscopy has a measuring range of approximately 3 nm – 3 µm. Therefore additionally laser diffractometry is used to detect any content of particles in the micrometer range or aggregates of drug nanoparticles. An additional analysis by Coulter counter technique is essential for nanosuspensions to be administered intravenously. The Coulter counter gives absolute data (i.e. absolute number of particles per volume unit for the different size classes) and not limiting in its range. Differential scanning calorimetry can be used as a tool to assess the crystalline structure of the nanosuspensions
[10].

This is especially important when different polymorphic forms of a drug exist.

It is important to determine dissolution velocity to assess the benefits compared to the traditional
drug formulation for example, coarse powder or a micronized
product. To determine the dissolution velocity, the
methods described in the Pharmacopoeia can be used
for example;
for determination of the saturation solubility
shaking experiments at different temperatures (4, 20, 40 ºC) need to be performed until equilibrium has
been reached. Increased
dissolution velocity and increased saturation solubility — apart from the adhesive properties of nanosuspensions — are the basic benefit of nanosuspensions compared to traditional dosage forms. These parameters allow estimation of the change in pharmacokinetic performance of the drug to a large extent.

Some additional parameters need to be determined for intravenously injected nanosuspensions, which affect the in vivo fate of the drug nanoparticles. Surface hydrophilicity / hydrophobicity are considered as one of the important parameters affecting the in vivo organ distribution after i.v. injection. The surface hydrophobicity determines the interaction with cells prior to phagocytosis

[11,12]

; also, it is a relevant parameter for adsorption of plasma proteins
[13,15–17]
. The qualitative and quantitative composition of the protein absorption pattern, observed after i.v. injection of the particles, is the essential key factor for organ distribution
[14–16-19]
. The protein analysis by 2-D PAGE was modified and especially adapted to the analysis of protein adsorption patterns on nanoparticles

[14]

Time-dependent adsorption patterns of proteins on nanoparticles were determined after incubation of polymeric particles with plasma or serum

[14,20-21]

, but also after collection of i.v. injected particles in animals

[22-23]

. Basic correlations could be established between the protein adsorption patterns and the organ distribution, here reflected by MPS cell uptake, certain particles circulating in the blood

[20]

, particles taken up by the bone marrow, and particles delivering drugs to the brain

[21,24]

. These established correlations can be fully exploited to produce in a controlled way target-specific nanosuspensions.

The uptake of i.v. injected nanoparticles by MPS cells is a natural phenomenon. The particles are recognized as being foreign and phagocytosed by the macrophages, mainly in the liver (60–90%), the spleen (approximately 1–5%) and to a very small extend by the lung macrophages
[17]
. This targeting has been called ‘natural targeting’ in the literature for the reason that it is a natural process. Depending on the nature of the surfactants used, sometimes it takes 15–30 min
[17]

. This might be too long for many nanosuspensions of drugs. The surface properties need to be changed in a controlled way such that preferentially adsorbed proteins can mediate the uptake process by macrophages. Therefore, the surface properties of the nanosuspensions need to be adjusted this way, so that fast recognition and uptake takes place.

Physical, Chemical and Biological properties of nanosuspensions

The increase in the saturation solubility and consequently an
increase in the dissolution velocity (due to increase or enlargement of surface area) of the compound are an outstanding feature of nanosuspensions. Basically, the saturation
solubility is a compound-specific
constant depending only on the temperature. In case
of polymorphism, the saturation solubility depends
also on the crystalline structure (i.e. the inner
energy). However — apart from temperature and crystalline / amorphous status — the saturation solubility is also a
function of the particle size. This size-dependency
comes only into effect for particles having a size
below approximately 1 µm.

Another marked property is the adhesiveness generally described for nanoparticles

[25]

. There is a distinct increase in adhesiveness of ultra fine powders compared to coarse powders. This adhesiveness of small drug nanoparticles can be exploited for improved oral delivery of poorly soluble drugs. Improved bioavailability, improved dose proportionality, reduced fed / fasted variability, reduced inter-subject variability and enhanced absorbtion rate (both human and animal data)

[26]

are some of the important benchmarking effects of a drug formulated as nanoparticles in oral administration. These data have been acquired in vivo in animals but also in humans as reported by the company NanoSystems. A drastically remarkable report is that of the increase in bioavailability for danazole from 5 % (as macrosuspension) to 82% (as nanosuspension)

[26-27]

.

A potential change in the crystalline structure of nanosuspensions saying increasing the amorphous fraction in the particle or even creating completely amorphous particles is a characteristic of consideration. The application of high pressures during the production of nanosuspensions was found to promote the amorphous state

[28]

. The degree of particle fineness and the fraction of amorphous particles in the nanosuspensions were found to be dependent on production pressure number of cycles and hardness of drug. The increase in the amorphous fraction leads to a further increase of the saturation solubility. With the use of homogenization process (giving uniform particle size), a special feature of Ostwald ripening

[29]

is overcome which means physical long-term stability as an aqueous suspension

[30-31]

.

In oral drug administration, the bioavailability and finally its efficacy depends on the solubility and absorption in the gastrointestinal tract. In vitro, highly active compounds have failed in the past because their poor solubility has limited in vivo absorption and did not lead to effective therapeutic concentrations. As an example, Atovaquone is given orally three times 750 mg daily, reflecting a high dose as an antibiotic. The main reason for the high dose is the low absorption— only 10–15%. Oral administration of nanosuspensions can overcome this problem because of the high adhesiveness of drug particles sticking on biological surfaces and prolonging the absorption time. These results reflect the potency of this technique, reducing drug load from 22.5 mg/kg to 7.5 mg/ kg, but increasing activity almost three fold at the same time.

The adhesiveness of nanosuspensions can not only be used to improve bioavailability, it is also a smart way for drug targeting of parasites persisting in the gastrointestinal tract. In short, oral administration of nanosuspensions is a drug delivery strategy, not only to improve bioavailability, but also to target gastrointestinal bacterial and parasitic infections. Nanosuspension technology is considered as suitable new colon delivery systems for the treatment of colon cancer, helminth infections, gastrointestinal inflammation or GIT associated diseases like sprue (zoeliaki). Infections like tuberculosis, listeriosis, leishmaniasis, and toxoplasmosis are caused by parasites
residing the macrophages of the MPS, thus being relatively easily accessible by i.v. injected particles. The i.v. injected particles are heavily and quickly taken up by the MPS cells in case they absorb uptake promoting proteins like apolipoproteins. However, some parasites do also reside in the brain (CNS). The brain-localized parasite mostly leads to relapsing infections if not cured. Therefore, it would be of importance to target drug nanoparticles via surface modification to the brain.

A successful targeting of the peptide, dalargin, to the brain using Tween 80® surface modified polyisobutylcyanoacrylates nanoparticles has been reported by Kreuter et al.
[32]

The mechanism was identified as being ApoE-mediated and was confirmed for the nanosuspensions.

Parenteral route of drug administration is critical, i.e. usually accompanied by physical and biological problems, like production under aseptic conditions, a sophisticated protocol for safety issues, and, last but not least, biological problems, such as endotoxins, allergic reactions, and inconvenience for the patient. Parenteral administration also has its advantages. A simple but effective drug targeting principle is to deliver the drug to infected macrophages. Colloidal drug carriers systems have attracted interest for many years in their ability to incorporate different drugs in microparticles, liposomes, polymer particles, microemulsions thereby exploiting this natural uptake mechanism.

Applications of nanosuspension technology

Pure drug nanosuspensions can play a critical role as an enabling technology for poorly water-soluble and/or poorly permeable molecules having significant in vitro activity. Such molecules pose problems at any or both of the following during new drug development activities: (1) formulation of an intravenously injectable product for preclinical in vivo evaluation of the new molecule to measure its toxicity and other pharmacokinetic characteristics and (2) poor absorption of the drug candidate from the GIT resulting into poor bioavailability during preclinical as well as clinical development studies. Pure drug nanosuspensions can provide solutions to both of these problems. A pure drug nanosuspension contains pure drug particles suspended in an aqueous media. As the particle size (usually below 400 nm) is way below the minimum particle size that can be administered intravenously (ie, 5 µm), a nanosuspension can be administered intravenously to conduct exploratory study with the candidate drug molecules.
[33]

Nanosuspension helps in administration of huge drug concentration of poorly water-soluble drugs to brain with decreased systemic effects. Thus nanosuspension has application to various route of administration like parenteral, oral topical, pulmonary and targeted drug delivery system.

Summary

The drug nanoparticles irrespective of the method of production represent a technology to overcome solubility problems and bioavailability problems of all poorly soluble drugs. The transformation of any drug to drug nanoparticles leading to an increase in saturation solubility, dissolution velocity, and providing the general feature of an increased adhesiveness to surfaces is one of the most important achievement. Surface modification of the drug nanocrystals can further increase the benefits, by producing mucoadhesive nanosuspensions for oral application (e.g. targeting to the stomach or colon) or surface-modified site-specific nanoparticles for intravenous injection (e.g. targeting to the brain, bone marrow etc.). A fusion of the novel nanosuspension technology with the traditional dosage forms, e.g. incorporating drug nanoparticles into pellets or tablets for oral delivery is also a note worthy advantage. Thus, these poorly soluble and poorly bioavailable drugs so called “brick dust” candidate once abandoned from formulation development can be rescued by formulating into nanosuspension which is a simple technology having a higher chance to launch products on the market.

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About Authors

Jignyasha A. Raval*, Jayvadan K. Patel, Madhabhai M. Patel

Shree S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Gujarat, India.

Jignyasha A. Raval

{cb_profile=Jignyasha}Jignyasha A. Raval{/cb_profile} currently working as a lecturer in the Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-382711, Gujarat, India, has an experience of four and a half years in documentation and Quality Assurance at Torrent Pharmaceuticals Ltd., Gujarat, India.

E-mail-jignyasha26@gmail.com

Dr. Jayvadan K. Patel

{cb_profile=jayvadanpatel}Dr.Jayvadan Patel{/cb_profile} is an Assistant Professor since the last ten years, Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-382711, Gujarat, India.

E-mail-jayvadan04@yahoo.com

Dr. Madhabhai M. Patel

Dr. Madhabhai M. Patel is Principal and Head of Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-382711, Gujarat, India.

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