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.
Summary:
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.
Ref:
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.
http://www.mentorconsulting.net/publications_files/Russell-Jones%202011%20WOW%20transdermal.pdf
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.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.