The term “microemulsion” often used to describe a variety of micellar structures from simple droplets to complex cubic compositions. In this discussion, the classic definition is assumed: a thermodynamically stable colloidal dispersion of water and oil stablized by a surfactant, and often, a co-surfactant. In comparison with coarse emulsions, microemulsions form spontaneously, are clear or transparent, have smaller droplet size (<150nm), and have lower interfacial energy.

Interest in microemulsion formulations spans the cosmetic and pharmaceutical industry because of potential for lower skin irritation, drug permeation enhancement, cosmetic properties, and drug solubilization. With increased interest in microemulsions, formulation improvements are being reported at an increasing rate. For example, microemulsions have historically included a low-to-medium-chain-length alcohol as a co-surfactant. When applied to skin, these formulations often caused irritation and dehydration. In recent years, more cases of alcohol-free microemulsions have been reported with much lower irritation potential.

The thermodynamic stability of microemulsions can contribute to improved formulation stability relative to conventional coarse emulsions by their lower potential for phase separation, creaming, flocculation, or increased droplet size (”Ostwald ripening”). This advantage can yield increased formulation robustness when challenged by prolonged temperature excursions. The favorable thermodynamic stability of microemulsions also can lead to simplified pharmaceutical product development, scale-up, technolology transfer, and manufacture. This is due partially to the lower energy input requirement to achieve the microemulsion. Simpler, low-energy mixing equipment may be adequate to prepare microemulsion formulations. In contrast, coarse emulsions often require the addition of heat, preparation of multiple side phases, and the use of rotor-stator homogenizers or high pressure microfluidization process equipment. In some cases, the low viscosity of microemulsions presents a challenge when formulating topical products because of the need to retain the drug at the application site. In these cases, it may be necessary to add viscosity modifying excipients to form a microemulsion gel formulation.

The mechanism by which microemulsions may enhance drug permeation in skin is not clear. Increased permeation may be due to several mechanisms, including: higher drug solubility in the vehicle providing a greater reservoir of drug in the vehicle; permeation enhancement properties due to one of the formulation components; and improved wetting of the skin surface due to lower interfacial tension.

In summary, microemulsion technology has advanced significantly and is a viable formulation option for topical and transdermal drug delivery products for drugs with appropriate physicochemical characteristics and therapeutic endpoints.

As the questioner points out, there are benefits to dosing drugs with consideration of the normal and cyclical rhythms of human physiology. Examples where disease conditions show cyclical patterns that correlate with circadian rhythms include:

Epilepsy: Seizures may occur only at particular times of the day or night

Allergies: Symptoms of sneezing and stuffy nose are typically worse in the morning waking hours

Asthma: Symptoms are more likely to occur in the hours prior to awakening

Rheumatoid arthritis: Pain is often most intense upon awakening.

Osteoarthritis: Symptoms typically worsen in the afternoon and evening.

Angina: Symptoms are most common during the first several after awakening.

Heart attack: Occur most commonly occurs in the early waking hours

Stroke: Most commonly occur in the early waking hours

Diabetes: Insulin levels and the counterregulatory hormones that work against the actions of insulin are in turn, influenced by the circadian rhythm.

Chronotropic drug therapy has been in the physician’s bag of treatments for decades. “Alternate day therapy” has been an option for administration of corticosteroids (e.g., prednisone) for treatment of asthma, rheumatoid arthritis, or other indicated diseases. In this practice, the dose is administered in the early morning every other day. The benefit is to minimize supression of adrenal function and the associated adverse events found in long-term therapy of corticosteroids.

Currently, there are a number of commercially available oral drug-delivery platforms targeted for chronotropic therapy. Applications include delayed-release oral technologies that are administered in the evening and delay the release of antihypertensive drugs until the early morning hours when there are normal increases in heart rate and blood pressure. In addition to oral platforms, parenteral chronotropic systems are experiencing increased utilization. The most widespread application is that of the insulin pump, which is used to administer insulin for the treatment of diabetes mellitus. With the insulin pump, patients can customize insulin delivery to meet their particular requirements. Newer applications of chronotherapy are being reported. For example, time-scheduled regimens for cytotoxic drug delivery by intravenous infusion based on a pharmacokinetic–pharmacodynamic model have been reported.

Historically, the study of circadian rhythms and related treatments in medical schools has been limited. With increased knowledge of the physiological basis, therapeutic benefits of chronotherapy, and advances in drug-delivery technologies, we can expect to see increased application of drug-delivery technologies to chronotherapy.

Yes. Inquiries to our organization which involve preclinical programs where dosing levels have reached and, perhaps, exceeded limits for reasonable administration have increased. A reasonable explanation may be the increased percentage of new drugs with challenging biopharmaceutical properties. In a recent scientific forum, it was estimated that only 10% of new drugs meet the criteria for high solubility, with the majority of new drugs displaying low solubility, low permeability, or both. In addition, strained budgets and accelerated project timing pressures seem to encourage more risky development strategies. This situation can reach a crisis point where a formulation solution is sought as a quick fix. Unfortunately, it is common that critical biopharmaceutical data (e.g., permeability, solubility, Log P/D) are not available to serve as a guide for the formulation effort. The early acquisition of data that identifies bioavailability limitations (e.g., solubility, permeability) can be critical to the development of optimized formulations with potential benefits for lower API demand and cost, increased bioavailability, and more rapid drug product development.

We can look at the progress made in the oral delivery of insulin and predict similar successes for oral delivery of insulin analogues. Numerous technologies have been applied to oral insulin delivery to overcome the two primary obstacles: degradation and low membrane permeability. Examples of these technologies include enteric coatings, micro- and nano- particulates, mucoadhesives, liposomes, permeation enhancers, and others. In many drug-delivery systems, multiples of these approaches are combined in a single platform. The fruits of these efforts are meeting the marketplace as shown by Oral-lyn, a spray buccal delivery system from Generex Biotechnology. Oral-lyn is available for sale in Ecuador, was approved in India in 2007, and is in Phase III clinical study in the United States, Canada, Russia, and several other countries. In late 2009, Novo Nordisk initiated a Phase I clinical trial of its oral insulin analog, NN1952, using the GIPET (Gastrointestinal Permeation Enhancement Technology) platform from Merrion Pharmaceuticals. The GIPET technology platform is a patented system that utilizes enteric coating and GRAS permeation enhancers to increase intestinal absorption of NN1952. We can expect the application of drug-delivery technology to the oral delivery of insulin analogues to accelerate.