Description of Research Work The main focus of the research group headed by Dr. Bozena B. Michniak is in the area of biological membrane drug transport and delivery. A large part of the work involves topical and transdermal drug delivery however, buccal as well as uterine tissue drug delivery are also being investigated. The research studies include dermatopharmaceutical approaches to formulation optimization and targeting of drugs and other agents transdermally or locally to layers within the skin. Examples of approaches used include the enhancement of transdermal drug delivery using chemical (chemical enhancement, partitioning, supersaturation) and / or physical means (iontophoresis, microneedles) as well as drug targeting using carrier systems and chemical retardants. Structure-activity relationships have been investigated for over 250 novel chemical agents with both dermal enhancing and retarding properties. The work includes molecular and computational modeling as well as modeling of stratum corneum lipid layer interactions with the compounds. Drug permeability pathways and effect of agents as well as iontophoresis on skin membranes are being investigated using radiolabeling techniques, confocal microscopy as well as SEM, TEM, Raman spectroscopy, DSC and FTIR.
The potential uses for retardants include sunscreen and other cosmetic formulations, insecticides and protective barrier creams for chemical warfare agent exposure. Chemical enhancers may be used in transdermal drug delivery systems to allow increased drug permeation into and across the skin thereby decreasing the amount of drug needed in the formulation as well as decreasing side-effects and offering more controlled delivery of the therapeutic agent. The permeability of both small molecular weight compounds (steroids, non-steroidal anti-inflammatories, antihypertensives, antibacterials, insecticides, sunscreens, etc.) and large molecular weight compounds (antisense oligonucleotides) are being studied.
Another area under investigation involves the tissue engineering of skin, and a human full-thickness skin co-culture of fibroblasts and keratinocytes using collagen as a dermal matrix, has been developed and been shown to possess similar drug permeability to human skin in vitro. The aim is to develop this bioengineered human skin as a screen for examining skin barrier properties, as well as a model for inflammatory and cytotoxicity testing. Projects include evaluation of correlations between the drug permeability, stratum corneum lipid composition, growth media compositions, pharmacology, and morphology and gross structure of the bioengineered skin. In addition, in vivo pharmacokinetic studies in rodents and weanling pigs have been conducted with drugs administered by several routes (topical, intravenous-infusion, bolus, and oral). A USP dissolution apparatus is available to record the dissolution parameters of oral (tablets and capsules) as well as semi-solid pharmaceutical preparations.
Background on Drug Delivery using Skin
The skin is a complex membrane that performs many physiological functions such as metabolism, synthesis, temperature regulation, and excretion. Its upper layer, the stratum corneum, is considered to be the main barrier to the percutaneous penetration of exogenous materials. This barrier is also important in the maintenance of water within the body as well as in the absorption of pharmaceutical and other agents. There are several categories of pharmaceutical products which are targeted to the skin or utilize the skin as a port of entry into the body and these include transdermal drug delivery systems (patches), gels, creams, ointments, lotions, as well as subcutaneous implants and dermal vaccinations. In contrast to the traditional oral route, the use of transdermal drug delivery by-passes first pass metabolism of the liver, the acidic environment of the gastrointestinal tract, and problems of absorption in the stomach which often contains food resulting in erratic and pulsed delivery of drugs into the intestine and variability in plasma concentration-time profiles. As with other routes of delivery, transport across the skin is also associated with several disadvantages, the main drawback being that not all drugs are suitable candidates. A number of physicochemical parameters have been identified (such as molecular weight) that influence the diffusion process, and variations in permeation rates can occur between different skin models, patients, different races, and between young and old. The major challenge is overcoming the resistance of the skin to permeation in a reversible and non-damaging manner as well as the design of therapeutically effective topical and transdermal formulations.
General Capabilities
- Conducting in vitro drug permeability studies in diffusion cells using human skin (biopsy, cadaver) or other animal skins (hairless mouse, rate, guinea pig, weanling pig). Polymeric membranes have also been used.
- Conducting in vivo studies with rodents (rats and mice) for drug pharmacokinetics following topical application. Irritation studies in vivo in small rodents follwed by histopathological examination of skin sections.
- Design and testing of pharmaceutical topical and transdermal formulations (creams, gels, ointments, lotions, suspensions, solution, transdermal delivery systems).
- Analytical testing: HPLC with diode array, UV/Vis detection and scintillation counting. Method validation and assay development.
- Fully functional chemical (organic and polymer) synthesis laboratory is also available. Over 90% of our novel dermal enhancers are synthesized in house, including Azone (laurocapram).
- Laboratory fully accredited and approved for radioactively labeled drug use, animal use, and human tissues/plasma/blood sample use.
Expertise Relating to Skin Research
- In vitro and in vivo skin permeability testing and skin content quantitation of applied drugs, formulation excipients, and cosmeceuticals.
- Skin permeability testing in vitro and in vivo of topical and transdermal formulations. Estimation of partition coefficients.
- Optimization of topical and transdermal formulations: vehicles, enhancers, drug carriers (nanoparticles, microspheres, liposomes, unimolecular micelles, etc). Use of physical enhancement techniques: iontophoretic and microneedle approaches.
- Design, synthesis, and testing of dermal penetration enhancers and retardants. Structure-activity relationships and molecular and computational modeling of compounds
- Stability testing of topical and transdermal products (temperature, light etc.).
- Dissolution testing for topical and oral dosage forms using the USP Dissolution Apparatus
- Analysis of skin distribution and content of drugs using skin stripping technique. Examination of skin transport pathways using biomarkers and /or confocal microscopy, Raman spectroscopy/ FTIR/DSC, etc.
- Examination of skin structure using light, confocal, electron (TEM, SEM) microscopy.
- Lipid / ceramide component analysis of the skin/stratum corneum using TLC techniques
- Production of a full thickness human bioengineered skin equivalent. Maintenance of normal and transformed keratinocytes and fibroblasts.
- Conducting full ADME (absorption, distribution, metabolism, excretion) studies in vivo and pharmacokinetic evaluations.
