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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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