Formulation Factors. Other Considerations. Transdermal Drug Delivery

Transcription

1 Formulation Factors and Other Considerations in Transdermal Drug Delivery Thomas S. Spencer, Ph.D. Becwar-Spencer Associates, LLC Bellingham, WA USA

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9 Enhancers Act on Lipid Bilayers O O= NH NH O= O O=NH O NH O O=

10 In Vitro Skin Permeation Cell Donor solution Skin membrane Receiver Cumulative Penetration Slope = Flux Time ( hours )

11 Fickian Diffusion Equation J Skin = K D (C s C i ) δ K = donor/skin partition coefficient Lipophillicity D = stratum corneum diffusion coefficient Molecular weight (size and polarity) δ = stratum corneum thickness C = concentration (donor surface - receiver)

12 Skin Permeation in Man Anatomical Variation Ratio to Arm Parathion Malathion Hydrocortisone Arm Abdomen Axilla Palm Forehead Scrotum Maibach,1971

13 Relative Skin Permeability Comparison Ratio of Animal Skin to Human Skin Ratio to Human Skin Penetration Rat Ratio Rabbit Ratio Pig Ratio Man (Ratio = 1) 0 Haloprogin Cortisone Butter yellow Acetylcysteine Caffeine Testosterone Data adapted from Bartek et al., 1972

14 Enhancers and Skin Irritation Bup-4 4 Anti-emetic Vehicle Skin Flux Irritation Propylene glycol Transcutol n-glycol PGML:EtOH 40: Bu:PGML:EtOH 5:25:70 Bu:PGML:EtOH 25:25:

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16 In Vitro Skin Permeation Buprenorphine Development Example Enhancer Flux Factor PG 0.35 ± PG:EtOH (9:1) 0.28 ± PG:Gly oleate(9:1) 1.5 ± PG: oleic acid(9:1) 2.2 ± PG: methyl laurate (9:1) 2.8 ±

17 Buprenorphine Matrix In Vitro Skin Permeation Skin Flux PGML- 7.5% +0.5 Capric Acid +0.5 Lauryl Alcohol Lauric Acid Roy et al.,jpharmsci 83: (1994)

18 TDS Matrix Composition Skin Contact Adhesive- skin adhesion Drug- extended steady state drug delivery Drug Penetration enhancer Plasticizer enhancer- promote drug delivery Plasticizer- increase adhesion Stabilizers- Crystal inhibitor, drug stability Stabilizers

19 Transdermal Film Components Backing Film Properties Impermeability to drug/enhancers Dimensional stability & conformation to skin Protection of drug matrix during wear Pliability for conformation to skin Release Liner Properties Impermeability to drugs/enhancers Protect the matrix prior to wear Release cleanly from adhesive matrix

20 Marketed Transdermal Designs Liquid Reservoir with skin contact layer(s) Matrix reservoir with skin contact layer Skin contact Matrix (drug and adhesive) Gel reservoir in contact with skin

21 Habitrol Transdermal Nicotine One day smoking cessation Backing Nicotine Oriented matrix Release liner Adhesive

22 Nicoderm Transdermal Nicotine One day smoking cessation Backing Adhesive matrix Support webbing Release liner

23 Nicotrol Transdermal Nicotine 16 Hour smoking cessation Polyester backing PIB matrix Release liner

24 Nicotine Transdermal Systems

25 Commercial Nicotine Patches Device Nicotrol Matrix Nicoderm Matrix Habitrol Reservoir Prostep Gel Duration Waking 24h 24h 24h Skin irritation 7% 14% 17% 22% Insomnia 1-3% 23% 3-9% 3-9% Headache 3-9% 29% 17% 11%

26 Vivelle-dot Formulation 3.5 Day Estradiol Hormone Replacement (1) Backing (2) Adhesive Containing Estradiol (3) Protective Liner (1) Translucent polyolefin film (2) Acrylic and silicone adhesive containing estradiol, NF, povidone, USP and dipropylene glycol (3) Polyester release liner

27 Pharmacokinetic Profile for Dot

28 Methylphenidate TDS Daytrana Daytime Attention Deficit Disorder Backing film Silicone-acrylate matrix Release liner Adhesive matrix composition Silicone Acrylic adhesive Durotak ( or ) Methylphenidate base 10-20%

29 Daytrana Methylphenidate Pharmacokinetic Profile Plasma conc ( ng/ml) 0 Time after Application (h) 24

30 Clinical and Regulatory Regulatory considerations-differences differences Polymer and enhancer suppliers- Non-USP Generic drug PK profiles- US vs Europe Topical vs transdermal Clinical considerations Pharmacokinetics-bioequivalence: C max AUC Skin toxicology Skin adhesion max &

31 Process Development and Manufacture Process: Rolls of backing films and release liners Polymer solutions Volatile enhancers subject to process loss Analytical methods & stability: >40 methods: : components, in-process & product Only drug substance methods are compendial Manufacturing: Coating & laminating Die-cutting Pouching

32 Adhesive Coater Rewind for die cutting and pouching Drying Oven Laminator Backing Release Liner Adhesive matrix (drying)

33 Active Transdermal Delivery Systems Iontophoresis Heat assisted transdermal delivery Microchannel delivery-physical Sonophoretic delivery Electroporation - Rf or Field effect

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