Posts Tagged ‘water-in-oil’

Author, Editor: Tilda Barliya PhD

We previously started a discussion on Transdermal Drug Delivery system (TDDS), see: http://pharmaceuticalintelligence.com/2013/01/28/introduction-to-transdermal-delivery-tdd-system-and-nanotechnology/

We introduced the main aspects of the anatomy of the skin, the advantages and disadvantages of TDDS and the main factors that affect the efficacy of a TDDS and their different types. In this followup, will try to dig a little bit deeper and analyze some examples of TDDS already made it to public use. The first TDD patch to be introduced to the US market was scopolamine in 1979 (1a,1b) for prevention of nausea and vomiting associated with motion sickness and recovery from anesthesia and surgery. But the TDDS that revolutionized the transdermal market was the nicotine patch, which was first introduced in 1991 as a treatment for smoking cessation (1c). Since then there has been development of a number of different patches, including a testosterone patch for hypogonadism in males and combination patches of estradiol and norethindrone or levonorgestrel for menopausal symptoms. Figure 1 shows the global sales of TDDS products by segments.

However, there are many disease applications that are treated with peptide or protein preparations (ranging from 900 Da molecular mass to > 150,000 Da molecular mass), usually by means of injection, as they cannot be delivered via topical application at present. Dermal and transdermal delivery of large molecules such as peptides, proteins, and DNA has remained a significant challenge.

Several attempts have been made to develop topical formulations for macromolecules using a wide variety of tools such as using delivery enhancers, delivery vehicles, and different penetration methods. For instance, the chemical enhancers such as alcohols, fatty acids, surfactants, and physical enhancers such as microneedles, ultrasonic waves and low electrical current (iontophoresis) methods  have been examined to improve topical delivery of macromolecules. These techniques however, suffer from different obstacles, ranging from inverse correlation between size and transdermal transport up to variably due to solvent ions, cargo charge and pH.  Poorly water-soluble peptides and proteins, which can be more readily solubilized by the dual water/oil formulation may offset some of these disadvantages.

The majority of topically applied peptides and proteins cannot enter the circulation in the skin as there is no basal-to-apical transport of such molecules through the vascular endothelium, and as such they must travel in the lymphatics in order ultimately to reach the circulation.

In a recent paper, Dr. Gregory Russell-Jones and colleagues review the use of a microemulsion system to effectively deliver proteins through the skin (2).

Water-in-Oil microemulsions:

Microemulsions are  nanosized, clear, thermodynamically stable, isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a co-surfactant.  These droplets can ‘hide’ water-soluble molecules within a continuous oil phase and therefore enable the use of water-soluble therapeutic drugs for different diseases, that otherwise cannot be achieved by the transdermal route.

Microemulsion system may have the potential advantages in delivery because of their:

  • High solubilization capacity
  • Ease of preparation,
  • Transparency,
  • Thermodynamic stability,
  • High diffusion and absorption rates

Previous work, both in small animals and humans, has utilized microemulsions containing small hydrophobic molecules, or small ‘model’ hydrophilic molecules.  The validity of these models in measuring lateral movement of topically applied material is rather questionable. Whereas only few of the studies evaluated the efficacy of microemulsions as transdermal drug delivery systems and were shown for desmopressin, cyclosporine and folate analogue methotrexate ( ref 2). More notably are the advances in insulin delivery.

Diabetes for instance , is the most common endocrine disorder and by the year 2010, is estimated that more than 200 million people worldwide will have DM and 300 million will subsequently have the disease by 2025 (7). DM patients suffer from a defect in insulin secretion, insulin action, or both and therefore require a constant external administration of insulin to keep their sugar levels under control. Insulin is most commonly being administrated using a pen, a syringe, an automated pump and more recently using a patch to ensure a pain-free approach. Some of these patcesh are being evaluated in clinical trials.

As a different approach, the authors have evaluated the use of microemulsion to delivery different type of peptides such as IGF-1, GHRP-6 and Insulin in an obese mice model. Among the studies that were conducted they evaluated the effect of increasing the dose of topically administered insulin formulated in a water-in-oil microemulsion which was compared with subcutaneously administered insulin. It was possible to increase the dose of topically administered insulin from 10 to 100 µg as there was no reduction in serum glucose seen at this dose. By contrast, it was not possible to increase the dose of subcutaneously administered insulin owing to the potential of death through induction of hypoglycemia (2). These are very encouraging results!!!

The authors also noted changes in weight loss/gain of the mice upon treatment depending on the initial weight and which was consistent with the known anabolic effect of insulin. Presumably the greater effect seen with the topical insulin is due to the depot-like effect of this route of administration, leading to a longer stimulation of both adipocytes and muscle cells.

An exciting area of potential development is weight control management. The results using insulin, IGF-I and GHRP-6 given topically are particularly intriguing. Whether these results can be replicated in humans and whether the use of these drugs for potential treatment of obesity will be commercially viable will be particularly interesting to observe.


Effective peptide and protein delivery to the skin has received much attention in the pharmaceutical industry, with many companies developing a variety of delivery devices to force peptides and proteins into and across the epithelium of the skin. Despite these many attempts, effective delivery of high-molecular-mass compounds has at best been poor. The water-in-oil microemulsion system may overcome the water-impermeable barrier of the epidermis and allows for effective delivery of highly water-soluble molecules such as peptides and proteins following topical application.


1a. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995530/

1b. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=76671

1c. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=92761472-2bdb-4ef9-9c81-a39b1852d7e0

2. Gregory Russell-Jones and Roy Himes. “Water-in-oil microemulsions for effective transdermal delivery of proteins”. Expert Opin. Drug Delivery 2011 Invited review –  8, 537-546.


3.  Ellen Jett Wilson. “Three Generations: The Past, Present, and Future of Transdermal Drug Delivery Systems”


4. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/09/WC500132404.pdf

5. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM220796.pdf

6. http://onlinelibrary.wiley.com/doi/10.1111/cbdd.12008/pdf

7. Salim Bastaki. Diabetes mellitus and its treatment. Int J Diabetes & Metabolism (2005) 13:111-134. http://ijod.uaeu.ac.ae/iss_1303/a.pdf

8. http://sphinxsai.com/Vol.3No.4/pharm/pdf/PT=39(2140-2148)OD11.pdf

9. Dhote V et al. Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System. Sci Pharm. 2012 March; 80(1): 1–28.


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