Scientists recently demonstrated that biphasic vesicles—a lipid-based, topical delivery system—can deliver large-molecule or macromolecule drugs into the skin. Success with biphasic vesicles offers the potential for needle-free administration of many pharmaceuticals that could previously only be administered by injection.
Biphasic vesicles may help revive drugs shelved in the past due to problems with effective delivery. At the same time, biphasic vesicles enable the design of difficult-to-deliver molecules for a broad range of new drugs, allowing noninvasive and safe delivery through the skin.
The administration of drugs into the human body is dependent on several factors, including the active substance in question, its pharmacokinetic profile, and the desired location of action. Because they are noninvasive, drugs administered by mouth, by inhalation, or directly to the skin (dermally) are often preferred by scientists to those requiring injection into the circulatory system.
While these delivery methods may be preferable, they do have several disadvantages when compared to injections. For example, oral administration requires efficient absorption through the gastrointestinal (GI) tract. Therefore, a drug must be resistant to the harsh physicochemical environment present in both the stomach and the intestines.
The oral delivery of drugs also exposes them to first-pass metabolism within the liver; this often results in significantly reduced bioavailability; that is, the rate at which the active drug enters the systemic circulation.
The inhalation of aerosol drugs eliminates both exposure to the GI track and first-pass metabolism. However, the difficulty of metering dosage accurately, coupled with the requirement for complex delivery devices, generally limits the use of inhaled drugs to those targeting the lungs directly.
Cutaneous delivery of drugs is complicated because the skin acts as a barrier to external contaminants, and drug delivery often requires the use of some method of physical or chemical disruption.
Structure of human skin
The skin is composed of three primary layers: the epidermis, dermis, and subcutaneous tissue. The outmost layer of the epidermis, the stratum corneum, is a resilient barrier to absorption of macromolecules and even some small-molecules.
The stratum corneum is composed of anywhere from ten to sixty layers of flattened, nonliving corneocytes that are almost entirely made up of cross-linked keratin (75% to 85%). An intercellular matrix—composed primarily of long-chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate, and sterol or wax esters—surrounds the corneocytes.
Biphasic vesicles are complex structures that are unique in that they are a combination of different compounds including lipids, micelles, and emulsions. The average diameter of a biphasic vesicle is 1 µm to 10 µm depending upon the specific composition of the vesicle and the encapsulated drug. Biphasic vesicles contain aqueous oil—a stabilized cationic nano-emulsion with an average droplet size of 300 nm—and cationic surfactant micelles (average diameter of 50 nm) surrounded by concentric phospholipid bilayers (see figure 1).
Biphasic vesicles have an inherent ability to encapsulate a variety of therapeutic substances proportionately and are able to deliver drugs transdermally.
Preparation and process
Biphasic vesicles are complex and scientists most often produce them in a multistep process. The first steps are the creation of a lipid phase and an aqueous phase (see figure 2). The lipid phase consists of a hydrophilic solvent and hydrophobic lipids that are mixed together with a low-shear mixer. The aqueous phase is a two-step process that utilizes microfluidization to create an oil and water nanoemulsion. Microfluidization is a high-shear process that ensures that the emulsion is stable and uniform with an average droplet size that falls within a 200 nm to 500 nm range. This droplet size ensures the formation, stability, uniformity, and bioavailability of the biphasic vesicles.
During the development process, formulation scientists produce biphasic vesicles in small batches typical of laboratory-scale volumes. These amounts may be as small as a gram or less. Like most drug delivery systems, the process requires scalability for pilot- and production-sized batches. The microfluidization process enables the scalability of biphasic vesicles while also maintaining the integrity of the laboratory formulation throughout scale-up and industrial production.
Using biphasic vesicles
Delivery of drugs through the skin includes two classes that are associated with distinct purposes.
Dermal delivery. Dermal delivery involves delivery of a drug into the skin itself for dermatological treatments, vaccinations, or cosmetic applications.
Transdermal delivery. Transdermal delivery also uses the skin as the application site, but introduces the drug for transport into the circulatory system. The transdermally route of administration bypasses the GI tract, first-pass metabolism, and many of the complications associated with injectable drugs. Because the skin is extremely effective at protecting the body from external pathogens and toxins, however, formulation scientists must design both dermal and transdermal delivery systems to circumvent its barrier properties.
In general, scientists think that absorption into the skin occurs through an intercellular route, typical of lipophilic substances; the appendages (hair follicles and sweat ducts); or an intracellular route, more typical of hydrophilic substances.
In recent studies, researchers investigated the delivery mechanism of biphasic vesicles by using interferon alpha (IFNα), a protein used for topical treatment of human papillomavirus infections.1 They employed IFNα as a model protein to improve their understanding of both the interaction of biphasic vesicles with human skin and the transport of macromolecules through the stratum corneum (see figure 3).2
The work revealed that biphasic vesicles delivered IFNα intercellularly to a depth of 70 μm, which is well below the stratum corneum and into the viable epidermis. Data suggest that the interaction of biphasic vesicles with the stratum corneum lipids resulted in the formation of a three-dimensional cubic Pn3m polymorphic phase by the molecular rearrangement of intercellular lipids.3 The researchers believe that the formation of this cubic phase is unique to biphasic vesicles and could be an intercellular-permeation nanopathway that may explain the increased delivery of IFNα by biphasic vesicles.
Liposomes and nanoemulsions do not induce a cubic phase and they deliver low amounts of IFNα below the stratum corneum. The researchers hypothesized that induction of a Pn3m cubic phase in stratum-corneum lipids could also make dermal and transdermal delivery of other macromolecules possible.
Researchers continue to search for a more effective design for dermal and transdermal delivery systems. Despite the rapid growth of new delivery technologies, complications associated with the noninvasive introduction of drugs to the body remain. As of 2008, the U.S. Food and Drug Administration had approved only twenty transdermal drug formulations.
For dermal and transdermal delivery to become available for use with a wider range of next-generation therapeutic agents, ongoing work must establish a clear understanding of the mechanisms of barrier properties associated with these drugs.
Scientists studying the mechanism of delivery of biphasic vesicles observed that the structure of the vesicles is important, since its constituent ingredients, being liposomes and nanoemulsions, do not promote drug delivery. Further understanding of structural changes in the skin will allow more efficient passage of macromolecules into the body.
The pharmaceutical industry hopes that novel therapeutic biologics (macromolecular drugs) will fundamentally reshape the marketplace.4 This change will replace injections with a safer, noninvasive delivery method, such as that offered by biphasic-vesicle dermal delivery.
1. Foldvari M, et al. Biphasic vesicles for topical delivery of interferon alpha in human volunteers and treatment of patients with human papillomavirus infections. Curr Drug Deliv. 2011, 8(3):307.
2. Foldvari M, et al. Topical delivery of interferon alpha by biphasic vesicles: Evidence for a novel nanopathway across the stratum corneum. Mol Pharmaceutics. 2010; 7(3):751.
3. Shah JC, et al. Cubic phase gels as drug delivery systems. Department of Pharmaceutical Sciences, Medical University of South Carolina.
4. Biologics in the pipeline: Large molecules with high hopes or bigger risks? In: Biologics from Pharmacokinetics, Modeling, & Simulation. Clinical Pharmacology & Experimental Medicine. Zhou H, PhD, FCP, Section Editor. Centocor Research & Development, Malvern, Pennsylvania.
Filed Under: Drug Discovery