Improve Transdermal Insulin Delivery

Maybelle Cowan-Lincoln

Several techniques for penetrating the stratum corneum are being investigated

The first transdermally delivered medication, a nitroglycerin ointment introduced in 1954, was developed after it was observed that fewer angina attacks were reported in munitions workers who handled it than in the rest of the population. In the 1980s, a transdermal nitroglycerin patch was released, followed more recently by patches that deliver compounds like fentanyl, lidocaine, estradiol, and nicotine.¹
By the early 21st century, transdermal delivery products constituted a significant portion of the drug candidates under clinical evaluation. According to a 2008 estimate, more than 1 billion transdermal patches were manufactured around the world in that year.²
The transdermal drug delivery route is particularly desirable for the treatment of diabetes. More than 21 million Americans suffer from this condition, and the CDC forecasts an annual growth rate of 43%. Multiple studies have demonstrated that insulin-dependent patients would benefit from five to six insulin injections per day, but many are not willing to suffer that much discomfort. This results in a “compromise regimen” of two or three injections per day.
A recent study estimates that only 30% of patients with diabetes achieve good control of blood glucose levels (defined as HbA1c lower than 7%). Poorly controlled diabetes can result in short-term symptoms that include low energy and difficulty concentrating and long-term complications such as neuropathy, blindness, and amputation.³
Although transdermal insulin can provide more comfortable therapy, potentially improving patient compliance and therefore diabetes control, this delivery system is best suited to low molecular weight compounds: 100–500 Da. Insulin is a macromolecular compound: 5800 Da. Traditional transdermal methods like patches are not an option. To meet the challenge of moving insulin across the stratum corneum, several penetration enhancement techniques are being investigated.
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CASE STUDY: The Thinking Person’s Diabetes Management

Ultrasonically enhanced transdermal delivery has been demonstrated in preclinical studies to reduce blood glucose levels as well as subcutaneous injections.¹ Using this technology, a “smart” diabetes management system—a possible step toward the elusive goal of an artificial pancreas—is being developed by Penn State University.
Sponsored by the Army, this project endeavors to create a small, portable device to control blood glucose monitoring and deliver insulin transdermally. The system will work like the body—continually sensing the body’s condition and reacting with a sufficient drug dose to maintain a healthy blood glucose level.²
This novel device is composed of three parts:

• Blood glucose sensor;
• Closed-loop feedback controller to vary the insulin dose according to blood glucose levels; and
• Transdermal drug delivery mechanism.²

The insulin delivery device employs ultrasound generated by a 3 x 3 rectangular array of cymbal transducers, facilitating transport across the stratum corneum. The rectangular array has been proven more effective than earlier devices that employed a circular pattern.³ —MCL

References

1. Park EJ, Dodds J, Smith NB. Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection. Int J Nanomedicine. 2008;3(3):335-341.
2. Smith N, Pishko M, Gabbay R, Werner J. Closed-loop noninvasive ultrasound glucose sensing and insulin delivery. September 2007. Award Number W81XWH-05-1-0617. Available at: www.dtic.mil/dtic/tr/fulltext/u2/a477332.pdf. Accessed June 3, 2012.
3. Luis J, Park EJ, Meyer RJ, Smith NB. Rectangular cymbal arrays for improved ultrasonic transdermal insulin delivery. J Acoust Soc Am. 2007;122(4):2022-2230.

Microneedles Enhance Delivery

One option is microneedles. These projections, typically ranging in length from 25 µm to 2000 µm, physically breach the stratum corneum to facilitate drug penetration. Solid microneedles are being studied to evaluate how successfully they deliver pharmaceuticals using one of the following two methods:

• “Poke and patch”: An array of microneedles is inserted into the skin and then removed after a short time. The area is then coated with a drug-loaded formulation. However, because this is a two-step process, there are concerns about patient compliance. There are also safety issues regarding non-biodegradable microneedles, particularly those made of silicon, breaking off in the skin during the process.
• “Coat and poke”: Microneedles are coated with a drug formulation that is released into the body, where the coating dissolves after insertion.

A 2003 study at the Georgia Institute of Technology using the poke and patch method demonstrated that solid microneedles can significantly increase transdermal insulin delivery. In the trial, an array of 105 microneedles was inserted into the skin of three groups of live hairless rats for 10 seconds, 10 minutes, and four hours, respectively. A flanged glass chamber of Humulin insulin was adhered to the skin around the array and left on for four hours in all three groups. Blood samples were collected and tested for blood glucose levels.⁴

In addition to microneedles and ultrasound, formulation development is focusing on excipient research into penetration enhancers.

All groups demonstrated a significant decline in blood glucose levels compared with pre-treament, but the largest decrease was seen in the group whose microneedles were left in for 10 seconds. This supports the use of a technique involving brief pre-treatment with microneedles followed by a long drug treatment on the area.
Hollow microneedles have also been shown to be effective in the administration of insulin across the skin. Successful attempts at blood glucose reduction have been achieved in rats using both passive diffusion—an array of microneedles attached to a drug reservoir—and a mechanically driven device employing an electronically controlled drug dispenser.
More importantly, hollow microneedle delivery of insulin has been demonstrated in Type I diabetic humans. Microneedles were inserted to three depths—1, 3.5, and 5 mm. The needles were attached to a 3 mL syringe containing insulin and connected to a syringe pump. The microneedles inserted 1 mm into the skin demonstrated rapid insulin absorption and blood glucose reduction. The efficacy of this depth may be attributable to the layer of capillaries found at that level.
In response to safety concerns about fracturing microneedles, there is an increasing push to manufacture these systems using biodegradable materials, including maltose, galactose, and water-soluble polymers. Any fragments made of these materials would be broken down by skin enzymes. These technologies are currently being evaluated for the delivery of proteins and peptides such as insulin.
Another means to increase drug penetration is electroporation, a technique in which an electric pulse is applied to the skin in order to create transient aqueous paths that increase the permeability of the stratum corneum approximately fourfold. Recently, it has been observed that anionic lipids driven into the stratum corneum extend the finite life of these channels, increasing drug penetration. This theory was tested at Roswell Park Cancer Institute in Buffalo, N.Y., evaluating the transport of insulin across porcine epidermis. When electroporation was enhanced with 1,2-dimyristoylphophatidylserine, an anionic lipid, transport was increased by nearly eighteenfold.⁵
Sonophoresis uses low-frequency ultrasound (20–150 kHz) to increase the transport of insulin. The drug is either incorporated into the hydrogel coupler or applied to the skin in an aqueous solution. The ultrasound enlarges pores, which remain open in the skin for several hours, along with low-pressure air bubbles on the skin’s surface. When the bubbles collapse, they create microjets, propelling the insulin through the stratum corneum.⁶
Although sonophoresis shows promise for successful transdermal insulin delivery, traditional ultrasound devices are large and relatively immobile. A small portable device is needed before this delivery system is feasible.
In response to this need, a portable apparatus that uses hard lead zironate-titanate disks is being tested. These circular caps are 0.25 mm thick with a 12.7 mm diameter and a cavity depth of 0.32 mm. Nine of these “cymbals” were wired into 3 x 3 arrays, driven by a radio frequency waveform generator, digital oscilloscope, RF amplifier, and matching circuit. Through multiple rabbit experiments, it has been determined that this small device can likely deliver the same amount of insulin as a conventional ultrasound machine, resulting in a similar reduction in blood glucose levels.^7,8
In addition to technologies such as microneedles and ultrasound, formulation development is focusing on excipient research into penetration enhancers. An Australian pharmaceutical company, Phosphagenics, claims to have developed a novel transdermal insulin that has achieved positive results in preclinical trials. These innovations may change the lives of more than 200 million diabetes patients worldwide.⁹

References

1. Donnelly RF, Singh TRR, Morrow DIJ, Woolfson AD. Transdermal delivery applications. In: Microneedle-Mediated Transdermal and Intradermal Drug Delivery. Chichester, U.K.: John Wiley & Sons, Ltd; 2012:79-112.
2. Grice JE, Prow TW, Kendall MAF, Roberts MS. Electrical and physical methods of skin penetration enhancement. In: Benson HAE, Watkinson AC. Topical and Transdermal Drug Delivery: Principles and Practice. Hoboken, N.J.: John Wiley & Sons, Inc.; 2012:43-66.
3. Sadrzadeh N, Glembourtt MJ, Stevenson CL. Peptide drug delivery strategies for the treatment of diabetes. J Pharm Sci. 2007;96(8):1925-1954.
4. Martanto W, Davis SP, Holiday NR, Wang J, Gill HS, Prausnitz MR. Transdermal delivery of insulin using microneedles in vivo. Pharm Res. 2004;21(6):947-952.
5. Murthy SN, Zhao YL, Marlan K, Hui SW, Kazim AL, Sen A. Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation. J Pharm Sci. 2006;95(9):2041-2050.
6. Owens DR, Zinman B, Bolli, G. Alternative routes of insulin delivery. Diabet Med. 2003;20(11):886-898.
7. Park EJ, Dodds J, Smith NB. Dolse comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection. Int J Nanomedicine. 2008;3(3):335-341.
8. Snyder B, Lee S, Smith NB, Newnham RE. Ferroelectric transducer arrays for transdermal insulin delivery. J Mater Sci. 2006;41(1):211-216.
9. Barnes K. World’s first transdermal insulin shows promise. In-Pharma Technologist.com. June 19, 2006. Available at: www.in-pharmatechnol