Reshaping water for greater solubility

Published: 9-Feb-2010

Regina Nadborny, head of chemistry at Do-Coop Technologies, explains how water can be manipulated at a molecular level to help solubilise hydrophobic active ingredients.

Many active ingredients are hydrophobic and will not dissolve in water. But researchers have found that water can be manipulated at a molecular level to help solubilise some of these awkward compounds, as Regina Nadborny, head of chemistry at Do-Coop Technologies, explains

The ability of water to dissolve more substances than any other material once earned it the label "Universal Solvent". However, with the number of hydrophobic drug compounds increasing, the solubility obstacles have left many promising innovative materials high and dry.

Although it is one of the most abundant compounds on the planet, natural water has managed to keep a lot of secrets from scientists over the centuries. Its molecular and physical mechanisms are as mystifying as they are familiar: why does radiation in water take so long to decay? Why does hot water freeze faster than cold water? Why does water boil through a "hot spot. mechanism, instead of heating evenly? Why do gas bubbles rising through water wobble on their way to the surface?

As if that is not enough, the mysteries multiply with intracellular water, one of the most important elements in the in vivo environment, yet the least understood. This water makes up 70% of living organisms but has different physical and chemical properties compared with natural water. Among other things, intracellular water can manage both hydrophobic and hydrophilic compounds at the molecular level, interfacing with the lipid site receptors and the aqueous regions in a natural process that can only be envied by modern chemistry.

Our bodies take in significant amounts of natural water every day, a fact we all take for granted as essential. And yet, modern medicine cannot trace the process by which the water we drink is transformed into the unique compound that takes on such enviable properties.

Perhaps because this remarkable situation is so familiar, most pharmaceutical and biotech researchers have never considered the possibility that the oddities of natural water might hold the key to the mysteries of intracellular water. Instead, r&d has viewed both kinds of water as obstacles that hamper the use of new hydrophobic compounds.

In trying to formulate a hydrophobic API, the standard bridge over the water barrier is assumed to be a delivery vehicle other than water. Usually a DMSO liquid system is chosen to carry the drug candidate in the in vitro testing. Any water that can't be eliminated is reduced to an inert state, as bulk or lab water; and intracellular water (regarded as just more water) is not taken into the equation at all.

The price for this approach is paid - with interest - at the clinical stage. The toxicity of the DMSO forces researchers to switch the delivery system to an acceptable vehicle, which (not surprisingly) changes the drug performance. The new formulation shows no sense of obligation to follow the pre-clinical data of the old formulation, and the unpredictable clinical results often bring the research to a discouraging dead-end.

the dilemma

Today, the pharma industry is facing a major crisis as hundreds, if not thousands, of compounds with proven activity have been shelved because of this formulation problem and its dismal outcome. Billions of dollars have already been spent, with no possible ROI.

The attempt to recover some of that loss by "high throughput screening" (throwing the entire IP library at a new problem, in the hope of a lucky match) have not yielded promising results, but instead have added to the unrecoverable expenses of the company.

Instead of fighting water as an enemy of hydrophobic compounds, what if we were able to harness the unique properties of natural water to make it more like intracellular water? Couldn't this new "water" become an ally in drug solubility?

Researchers at Do-Coop Technologies, a private IP company based in Israel, suspected that these possibilities did exist, and they focused on understanding both kinds of water at the molecular level. Using the power of nanotechnology, they have applied that knowledge to turn water from a barrier into a liquid that mimics the intracellular water found in the human body. The result was dubbed "Neowater".

Neowater is a proprietary water-based nanotechnology that has succeeded in giving to natural water the properties observed in intracellular water. Just as nature uses intracellular water as a supporting environment for chemical and biological activities that are not compatible with natural water, Do-Coop Technologies has harnessed those same properties in the service of the same goal.

The unique organisation of the water molecules in Neowater is derived from interaction among the water, carbon dioxide and a suspended minute amount of insoluble nanoparticles (1015 particles per litre) arranged in clusters. The nanotechnology harnesses the surface effect produced by these nanoparticles and the elevated amount of insoluble carbon dioxide to create structure within the water and thereby reduce the entropy of the bulk.

This combination provides a much greater surface area and more closely resembles naturally occurring water in biological organisms, which plays a part in carrying and integrating hydrophobic compounds into living systems.

The molecular interaction of Neowater results not only in new and better formulation of hydrophobic drugs, but also higher stability of proteins and cell cultures, the enhancement of biological in vitro and in vivo reactions, and a reduced need for the introduction of stabilisers, detergents, co-solvents or surfactants.

formulation aid

Neowater provides formulation answers that are safe, bioavailable and cost-effective. Its structure is remarkably stable under both extreme and standard conditions (STP). And in solving the formulation problem, it eliminates the need for replacing a toxic drug delivery system in the middle of r&d, which guarantees consistent data throughout the testing process.

Neowater is composed of two hydrogens and one oxygen - the same basic chemistry as bulk water. The main difference is that water molecules in Neowater are organised in clusters and therefore feature different properties when compared with bulk water. The key feature is the clusters" very large surface area, which is achieved by introducing nanoparticles to the water via a proprietary process.

The production of Neowater starts with ultra-pure water (UPW) that is kept below the anomaly temperature (below 4°C) and is irradiated by radio frequency (RF) signal at 915 MHz at a power of 60 watts (Fig. 1). After 10 minutes of RF irradiation, a sub-micron sized powder of insoluble particles, which is heated to about 900°C, is dropped into the water and the irradiation continues for five more minutes. Most of the powder sinks to the bottom, and only the clear water is used.

Fig. 2 shows one of the most extreme cases when comparing the source powder of micron-sized hexagonal rods (A) with the resulting nanoparticles in Neowater (B). It can be seen that after the doping process, most of the particles that are suspended in the water range from 5-50nm in diameter, and they have almost perfect spherical shape, as though melted. It is during the production process that nanobubbles are generated by the RF treatment, which are then used for cavitation.

During this time the water goes through self-organisation that includes a gas exchange with the external atmosphere and selective absorption of the surrounding electromagnetic radiation. This leads to the formation of the stable structured distribution of the nanobubbles and the injected particles. The density is below 1012 nanoparticles/ml, and the distance between the nanoparticles is larger than 1µm.

The large bubbles (exceeding a critical radius) expand and float to the water surface, while smaller bubbles surround the larger ones, forming clusters in an ordered shell that is less hydrophilic than the water. Unlike large gas nanobubbles, these nanoparticles do not expand, providing totally stable anchors for the entire array of gas nanobubbles.

Neowater's post-production composition is distinct from regular water in that the CO2 concentration is up to 100-fold higher, and the enlarged surface area, due to the nanoparticles, provides structure in the liquid phase. These characteristics result in an enhanced ability to disperse both hydrophobic and hydrophilic compounds, while at the same time heightening bioavailability and efficacy. The vehicle is nontoxic, inert and compatible with intracellular water. It is also remarkably stable at STP.

added solubility

Given the fact that 40-50% of all new APIs get stuck within the drug development cycle because of hydrophobic issues, Neowater's value becomes self-evident. This applies not only to more successful r&d trials, but also for improved profit potential in the whole r&d endeavour.

With Neowater as the consistent aqueous vehicle, companies can streamline their drug development process, moving from in vitro development to in vivo delivery, and from early laboratory experiments to late-stage studies in humans, more quickly, more cost effectively, and with fewer unpleasant surprises. Better hydration, greater control in sustained release formulas, and longer shelf life are more documented side-benefits from the presence of Neowater.

Yet another bonus is Neowater's nontoxic certification by the US Food and Drug Administration (DMF# 20503), which serves to streamline any r&d project that initiates clinical studies using a Neowater-based formulation (no need for a separate Neowater toxicity control).

Do-Coop Technologies" production of Neowater is GMP compliant, and the company is currently in the process of having it certified as GRAS (Generally Recognized as Safe) by the FDA.

The Neowater vehicle facilitates compound formation in a manner unlike any other currently available system. However, because Neowater is a naturally generic solution, it provides an optimal vehicle structure for many compounds with only minimal customisation. This opens the way for new and extended IP, based on extended therapeutic windows.

To date, Do-Coop has successfully formulated numerous compounds with Neowater in partnership with companies, who award Do-Coop royalties and milestone payments only. It is the developing company that reaps the rewards of Neowater, and retains IP ownership for the resulting compound(s).

As nanotechnology itself has revolutionised the way biologists and chemists do their work, Neowater holds the same promise for the way they do their thinking. Dissolving the water barrier for hydrophobic compounds can open the way to many "impossible dreams", including the potential of returning to an era of blockbuster compounds and healthy pipelines for long-term r&d.

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