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Nanosuspensions in drug delivery

Key Points

  • Nanosuspension formulation technology has evolved to meet the needs posed by the numerous water-insoluble drug candidates emerging from high-throughput drug screening programmes that emphasize fit into hydrophobic receptor pockets.

  • Although there are numerous other technologies that can be used, nanosuspensions are ideally suited for drugs with a high crystal energy, which renders them insoluble in lipid as well as aqueous vehicles.

  • The solid state of the nanosuspension confers high weight per volume loading, which is ideal for depot delivery in which administration volume is constrained and high drug levels must be administered.

  • The reduced particle size entails high surface area, thereby increasing the dissolution rate to overcome solubility limited bioavailability.

  • Surfactants, utilizing electrostatic and steric stabilization mechanisms, coat the nanoparticles, thereby preventing their agglomeration and ensuring pharmaceutical stability.

  • Methods of manufacture involve crystallization, building nanocrystals up from the supersaturated solution state, as well as making larger particles smaller by homogenization or milling.

  • Pharmacokinetic profiles for injectables vary from rapidly soluble in the blood, to slowly dissolving, after which macrophage uptake and subsequent release greatly prolong drug delivery, while minimizing peak height. For several drug classes, this leads to improved safety, which permits higher dosing and improved efficacy.

  • Regional delivery confers increased efficacy to local target organs, while minimizing systemic toxicity, and has been demonstrated for the central nervous system, lungs and topically.

  • Numerous solubility-related issues in oral administration of drugs can be resolved, and include increased rate and extent of absorption, reduced variability of absorption, faster onset of action, higher peak drug level, improved dose proportionality and reduced fed/fasted effects.

Abstract

A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.

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Figure 1: Decision tree for selection of formulation approach.
Figure 2: Creation and stabilization of nanoparticles, from the perspective of surface energetics.
Figure 3: Potential energy curve for approach of two nanoparticles.
Figure 4: Engineering breakable crystals with a combination of microprecipitation and homogenization.
Figure 5: Schematic of aseptic microprecipitation/ homogenization process.
Figure 6: Trafficking of drug nanoparticles by macrophages, monocytes and neutrophils.

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Acknowledgements

Thanks to J. Kipp (Baxter Healthcare Corp.) for his input to figures 1 and 4.

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Competing interests

B. R. is employed by Baxter Healthcare Corporation which commercializes NANOEDGE a nanosuspension drug delivery platform.

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DATABASES

Entrez Gene

P-glycoprotein

Glossary

SOLID LIPID NANOPARTICLES

Sub-micron-sized spherical lipid carriers of lipid-soluble drug molecules. They are typically formed by heating an aqueous lipid mixture above the melting point of the lipid, adding drug, homogenizing, then cooling to freeze the drug within the the solid lipid spheres.

HIGH-THROUGHPUT SCREENING

An automated instrumental process for detecting the binding of tens of thousands of drug candidates to an isolated protein receptor target that mediates a disease process, thereby identifying worthwhile leads for development.

LOG P

Log of the octanol–water partition coefficient, which is a measure of a drug's lipophilicity. Defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Higher values imply greater lipophilicity.

WATER INSOLUBLE

Less than 0.1 mg per ml solubility in water.

CYCLODEXTRINS

5–8mer of cyclic linked amylose or glucan molecules that forms a hydrophobic interior to accommodate an insoluble compound, and a hydrophilic exterior to solubilize in water.

BIOAVAILABILITY

A measure of the rate and extent of drug absorption from an administered dose, expressed as a ratio to an intravenously administered dose.

ARRHENIUS EXPRESSION

A mathematical equation that relates the rate of a chemical reaction, k, to change in temperature, T: k = Ae−E/RT. E is the activation energy or barrier for the crucial step in the reaction, and R is the gas constant.

POLYMORPH

One of several distinct crystal packing arrangements, potentially having a different energy of formation and melting point than other polymorphic forms of the same molecule. Its formation might be favored in preference to other polymorphs by manipulation of temperature, solvent and degree of supersaturation.

MONOCYTE PHAGOCYTIC SYSTEM

(MPS) The system of cells deployed throughout the body tissues, derived from monocyte precursor cells, which functionally police interstitial fluid and blood for unwanted particulate contamination, removing them by phagocytosis.

CMAX

Highest drug concentration in a plot of the plasma drug concentration versus time.

AREA UNDER THE CURVE

(AUC). Area under the curve of a plot of plasma drug concentration versus time, measured after administration of a drug.

FED/FASTED EFFECTS

A difference in the absorption of a drug depending on the fed or fasted state of the test animal.

OSTWALD RIPENING

The tendency for a particle dispersion to grow in diameter over time, by a process in which the smaller particles dissolve preferentially, because of their higher solubility, with subsequent crystallization onto larger particles, making them even larger.

PHAGOLYSOSOME

A cytoplasmic vesicular compartment consisting of the union of a phagosome with a lysosome, containing enzymes and acid environment designed to digest microbial particles.

t1/2

Half-life of plasma drug concentration, a measure of the duration of action of a drug.

PHOSPHOLIPID-PEG

A molecule consisting of phospholipid covalently bonded to a polyethylene glycol polymer, used as a reagent to coat a drug or drug delivery vehicle with a polyethylene glycol (PEG) surface, thereby conferring longer blood circulation time.

PHAGOCYTOSIS

Process of removal of particulate matter, bacteria, viruses, degraded cell debris, and so on by any of several mechanisms (for example, complement activation, opsonization or receptor mediation) involving extension of the cell membrane to surround and engulf the object, followed by severance of the membrane leading to a distinct vesicle within the cytoplasm of the cell, termed the phagosome.

OMMAYA RESERVOIR

A system for the delivery of a flowable drug formulation to the ventricles of the brain, involving a compartment for containment implanted in a proximal subcutaneous location.

PEGYLATION

Coating, either covalently or by physical adsorption, a polyetheylene glycol polymer onto a drug molecule, surface or particle, rendering it less hospitable to the deposition of opsonizing proteins which mediate phagocytosis. Such coated drugs and particles typically manifest extended circulation times in blood.

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Rabinow, B. Nanosuspensions in drug delivery. Nat Rev Drug Discov 3, 785–796 (2004). https://doi.org/10.1038/nrd1494

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