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Developing and Optimizing Transdermal Delivery Systems
Terri Sebree
Advantages of Transdermal Delivery
• Avoids GI tract– Prevents first pass metabolism– Eliminates drug absorption issues with GI stasis
• Common with migraine, prior gastric surgery, diabetes mellitus
– Treats conditions associated with nausea and vomiting
• Reasonably constant delivery can be maintained (as opposed to peaks and valleys associated with oral and parenteral delivery)
• Reduces need for active administration (some patches applied for 7 days)
• For patches, dosing can be stopped by removal• Easy to apply, convenient administration
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Transdermal Market
• Global transdermal market forecasted to grow from $21.5b in 2010 to $31.5b by 20153
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$8.0
$12.7
$21.5
$31.5
$0.0
$5.0
$10.0
$15.0
$20.0
$25.0
$30.0
$35.0
2002 2005 2010 2015
U.S. Transdermal Market 2002 – 2015(1) Markets Addressed(2)
(In $USD
billions)
1 Jain PharmaBiotech report. Transdermal drug delivery-technologies, markets and companies. 2005.2 Frost & Sullivan, US Transdermal Drug Delivery Market, August 2006.3 PharmaLive Special Report: Transdermal Medicine Review and Outlook, September 2011
Transdermal DeliveryWhy it matters to Pharma
• Product line extensions – buprenorphine, rivastigmine, methylphenidate
• Delivery of NCEs with low bioavailability –rotigotine
• Effective delivery of NCEs for patients with GI conditions and/or syptoms
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First Generation Transdermal Systems
• Suitable for low‐molecular weight, lipophilic APIs which are efficacious at low doses
• Patches, gels, liquid sprays
• Delivery limited and controlled by stratum corneum
Second Generation Transdermal Systems
• Utilize chemical enhancers to increase skin permeability
• Balance must be achieved to optimize drug delivery and prevent skin irritation
• Testosterone Gel
– AndroGel® – isopropyl myristate
– Testim®‐ pentadecalactone
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Testim vs AndroPatch® – PK
• Testim significantly increased testosterone and DHT serum concentrations from baseline compared to AndroPatch (2 patches)
– Consistent findings at 30, 60, and 90 days
7McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003;91(1):69–74.
Testim vs AndroGel – PK
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Testim provided 30% higher serum testosterone levels compared to AndroGel with a similar safety profile.
Steidle, CP, New Advances in the Treatment of Hypogonadism in the Aging Male, Rev Urol. 2003;5(suppl 1):S34-S40.
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Testim Efficacy
Days of Treatment Lean Body Mass(Muscle) (kg)
Total Fat Mass (kg) % Body Fat
Baseline 61.6 29.4 30.9
Day 90 63.3 28.6 29.8
Change from Baseline 1.6 0.8 1.1
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At Day 90, mean increase from baseline in lean body mass and mean decreases from baseline in total fat mass and percent fat in Testim-treated patients was significant when compared to placebo-treated patients.
Testim Prescribing Information
Safety – Skin Irritation Testim vs AndroPatch
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The distribution of men with positive application-siteirritation scores at 30 (open bars), 60 (green bars) and 90 days (red stippled bars).
There were significant differences (P< 0.001) for each of the Testim vs Andropatch comparisons at each time.
McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int. 2003;91(1):69–74
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Disadvantages
• Undesirable physical properties
– Stickiness
– Fragrance
• “Black box” warning of secondary exposure to testosterone
– Adverse effect potential of transfer risk to children and women upon close contact with skin
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Active Delivery
• Iontophoresis
• Non‐cavitational ultrasound
• Microneedles
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Goal of these delivery systems is to enhance delivery across the stratum corneum while protecting deeper, living tissues.
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Iontophoresis
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compound
• Iontophoresis provides an electrical driving force for transport of compounds across stratum corneum
• Charged drugs are move via electrophoresis
Iontophoresis Delivery Design and Optimization
• In designing an iontophoretic delivery system:– Dose delivered, dosing frequency, and pharmacokinetic profile must be defined
– Early studies identify metals for electrodes, power source, design of patch (integrated power source or attachable power source)
– Formulation must be developed which allows ion delivery and protects skin
– Optimization studies define ionic strength, formulation, current density, and patch size and shape
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Optimization – Ionic Strength Parameters
• For iontophoresis to occur, the drug substance must be ionized– Both in solution and possess a charge
• Parameters affecting iontophoresis:– Molecular size and molecular weight of drug ion
• Optimum range smaller and hydrophilic
– Ionic strength and presence of other ions• If above range will decrease drug delivery as extraneous ions compete with drug ions
– Influence of pH• If above range will increase risk of vascular reaction
15Dhote V, Bhatnagar P, Mishra PK, Mahajan SC, Mishra DK. Iontophoresis: A potential emergence of a transdermal drug delivery system. Sci Pharm.2012;80:1-28.
Optimization – Current Density
• Current density is key factor in determining drug delivery, rate of delivery, and skin tolerability
• Current density is calculated by dividing current (usually in milliamps) divided by the drug delivery surface area (usually in cm2)
• Current density optimization studies must be conducted in vivo
– Porcine model most effective for evaluating current density and tolerability issues
– Studies should be conducted with formulation to be used in animal and human studies
16 1. Siegel SJ, O'Neill C, Dube LM, et al. A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharm Res. 2007;24(10):1919-26
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Optimization – Size and Shape
• Optimization studies in vitro and in vivo investigate size and shape of:
– Reservoir pad
• Oval, circle, rectangle
– Patch configuration
• Oval, rectangle, figure 8
– Electrodes
• Oval, candelabra, rectangle, circle
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Zecuity® Sumatriptan Iontophoretic Transdermal System
• Intelligent, active transdermal delivery
– Microprocessor supports highly controlled and consistent
delivery
• Multiple safety checks within seconds of activation
• Continuous feedback system throughout dosing interval
– Controls both the rate and amount of drug delivered
– No difference in PK regardless of age, race, or gender
– Simple for patients – press a button (no inputs or
adjustments)
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Zecuity Sumatriptan Iontophoretic Transdermal System
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Applied to upper arm or thigh.
Iontophoretic Device
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Reservoir Card
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Zecuity Pharmacokinetics
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Oral 100 mg tablet
SQ 6 mg
Nasal spray 20 mg
Zecuity
Zecuity
Sumatriptan Plasma Concentration Group Mean (95%Cl) Over Time
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Zecuity Human Factors Usability Study
• Zecuity can be assembled, applied, and activated successfully during a mild to severe migraine attack
• In a clinical study, all participants (96.9% with moderate to severe migraine headache pain) were able to assemble, apply, and activate Zecuity
• Patients with migraine rated Zecuity very high for ease of assembly and ease of application/activation.
23 Meadows, K., et al, Sumatriptan transdermal system (TDS) can be correctly assembled, applied, and activated during migraine attacks, Headache Journal 07 April 2014.
Zecuity Heat Study• External Heat Source: A heat effect study in 12 healthy adult subjects
demonstrated similar pharmacokinetic values without and with the application of an external heat source (400 C heat wrap placed over top of the ZECUITY TDS for the 4 hour dosing period).
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Sumatriptan Plasma Concentration Group Mean (95%Cl) Over Time
Zecuity patch worn for 4 hours with a heat wrap applied over top the patchZecuity patch worn for 4 hours without a heat wrap applied over top the patch
Freeman, JC, et al, A Phase I, Single Center, Open Label, Randomized, Single-Dose, Two Way Crossover Study to Compare Pharmacokinetics of Two Patch Applications With and Without Controlled Heat, American Headache Society, 54th Annual Scientific Meeting, Los Angeles, CA June 2012.
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Zecuity Efficacy
• Pain relief and nausea freedom two‐hours following patch activation
– Twice as many patients treated with Zecuity achieve freedom from headache pain compared to placebo
– 53% of patients treated with Zecuity achieved relief from headache pain compared with 29% for placebo
– 84% of patients treated with Zecuity were nausea‐free compared with 63% for placebo
25 Pivotal Phase 3 Data (HEADACHE October 2012)
Zecuity Safety
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Zecuity Placebo
Application site pain 26% 17%
Application site tingling 9% 16%
Application site itching 8% 7%
Application site warmth 6% 3%
Application site discomfort 6% 6%
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Allergic Contact Dermatitis (ACD)
• Defined as cases having higher irritation scores, a crescendo clinical course, or prolonged recovery
• Putative cases of ACD identified through medical safety review were combined with the cases reported as ACD
• For Zecuity, all putative cases were evaluated and classified by dermatology consultant and ACD specialist, Howard Maibach, MD, (University San Francisco) – ACD is expected diagnosis
• For Zecuity, two long‐term study results where at least 2 patches were applied:– Probable = 3%
– Probable and Possible = 8%
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Transdermal Delivery and Pro‐Drugs
• Prodrugs are an enabling technology to deliver drugs into circulation through the skin
• Transdermal delivery enables controlled and sustained drug release
• Pro‐drugs may allow delivery of current medications that cannot be transdermally delivered and create new intellectual property
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SKINCirculation
Outside
DrugPro
Drug
Pro
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Novel advanced transdermal technologies
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Dhote V, Bhatnagar P, Mishra PK, Mahajan SC, Mishra DK. Iontophoresis: A potential emergence of a transdermal drug delivery system. Sci Pharm.2012;80:1-28.
Conclusion
• Transdermal delivery is delivery system of the future
– Viable alternative to oral or injectable administration
– Non‐invasive technology
– Eliminate over or under dosing by continuous delivery of drug
– Self‐administration is possible
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