michniak transdermal and topical drug delivery I

human skin cross section

- stratum corneum

- dermatoepidermal junction

- when looking down on skin surface, cells are peeling off

- cross section of human stratum corneum looks like the inside of a croissant

epidermis cell type

- keratinocytes

layers of epidermis

- stratum corneum

- granular layer

- spinous layer

- basal layer

dermis major cell type

- fibroblasts in dermal matrix

additional components of the dermis

- langerhans cells

- melanocytes

- hair follicles

- eccrine sweat glands

- sebaceous glands

- adipocytes

- blood supply

- nerves

interfacial boundaries

- surface

- stratum corneum

- appendages

- viable epidermis

- dermis

- circulation

surface penetration routes

- drug dissolves, diffuses, and releases from vehicle

some treatments of surface

- camouflage

- protective layer

- insect repellent

- antimicrobial/antifungal

stratum corneum penetration routes

- trans epidermal

- partition/diffusion, stratum corneum

stratum corneum treatments

- emolliency

- keratosis [exfolients]

appendages penetration route

- transappendageal 2 routes

- pilosebaceous unit

- eccrine gland

appendages treatment

- antiperspirant

- exfolient

- antibiotic/antifungal

- depilatory

viable epidermis penetration route

- partition/diffusion

viable epidermis treatment

- antiinflammatory

- anesthetic

- antipruritic

- antihistamine

dermis penetration route

- partition/diffusion

dermis treatment

- same as viable epidermis

- antiinflammatory

- anesthetic

- antipruritic

- antihistamine

circulation penetration routes

- removal via circulation

circulation treatments

- transdermal

order of skin layers that a drug must go through

- surface --> epidermis --> dermis --> subdermal tissue

gradient of skin

- pH gradient since top of skin at pH about 5.2

- water gradient

- calcium gradient

maximizing transdermal drug delivery

- vehicle-drug interactions

- vesicles and particles

- horny layer modified

- horny layer bypassed or removed

- electrically driven procedures

vehicle-drug interactions

- drug and prodrug selection

- thermodynamic activity

- ion pairs and coacervates

- eutectic systems

vesicles and particles

- liposomes and analogues

- high velocity particles

horny layer modified

- hydration

- chemical enhancers

horny layer bypassed or removed

- microneedle array

- stratum corneum removed

- follicular delivery

electrically driven procedures

- ultrasound

- iontophoresis

- electroporation

- magnetophoresis

therapeutic window

- peaking and valley between toxic and minimum effective levels

- the ideal transdermal dose is in the middle of the toxic vs min therapeutic level

advantages of TDDS

- bypass first pass metabolism and GI incompatibility with pH, food, enzymes

- reduce side effects [better plasma concentration time profiles]

- predictable and extended duration of activity

- greater patient compliance

- enhances therapeutic efficacy

- reduction in frequency of dosing

- reversibility of drug delivery which allows removal of drug source

- minimizing inter- and intra-patient variability as compared with oral

- self-administration

- good in patients with nausea, etc

criteria for drug selection

- correct physicochemical properties

- crystalline drugs have low permeability compared to amorphous

- need potent drugs

- no long lag times

- no dermatitis

- clinical need

correct physicochemical properties

- low molecular weight/size

- melting point

- want low water solubility and high partitioning

why do crystalline drugs have low permeability

- they have high melting points

- slow dissolution

dermatitis

- irritant to skin

clinical need

- prolonged administration

- patient compliance

- reduction in dosage

- adverse reaction to non-target tissues avoided

release kinetics of TDDS

- not all are zero order although this is most preferable

- estraderm

- nitrodisc

- transderm-scop

estraderm (17-beta estradiol) order

- zero

nitrodisc (nitroglycerin) order

- first

transderm-scop (scopolamine) order

- mixed

classes of TDDS systems

- membrane permeation-controlled (reservoir) TDDS

- adhesive dispersion-type TDDS

- matric diffusion controlled TDDS

- microreservoir dissolution controlled TDDS

membrane permeation-controlled (reservoir) TDDS

- transderm-scop

- transderm-nitro

- clonidine-TTS

- estraderm

- androderm

adhesive dispersion-type TDDS

- deponit

matrix diffusion controlled TDDS

- NitroDur

microreservoir dissolution controlled TDDS

- Nitrodisc

marketed systems

- fentanyl-duragesic for chronic pain

- nitroglycerin-many... for angina

- scopolamine-Transderm-Scop- FIST EVER TDDS EVER MARKETED for motion sickness

- testosterone-Testoderm, etc for hypogonadism

plasma nitroglycerin levels vs drug reservoir surface

- positive linear graph

- transderm-nitro system farthest right

- SL second farthest right

- ointment, Deponit, and ointment is the third most right

- Nitro-Dur is around the same region, but more below the line than the rest of them

release rate

- refers to how much drug is released over a certain time from the patch

permeation rate

- rate of diffusion of active across the skin membrane

in vitro testing of drug permeation

- using human or porcine skin membranes

- placed in glass diffusion cells called Franz cells

- donor compartment has formulation placed in it of known weight/drug concentration

- receptor sampled over time

- flux graph plotted

- skin kinetic parameters recorded

flux

- cumulative amount/unit time

skin kinetic parameters

- lag time

franz diffusion cells components

- donor compartment

- O-ring

- membrane

- receptor compartment with sampling port for analysis

- pinch clamp

- optimal water jacket

pinch clamp connects

- donor compartment

- O-ring

- membrane

- receptor compartment

in vivo testing of TDDS

- use larger animal

- best is weanling pig

- skin similar in thickness and lipid organization of stratum corneum to human

- patches often applied to the back of animal

in vivo technique of TDDS

- gauze pad with taped edges on top of window screen

- window screen on top of foam pad

- foam pad on clipped skin surface

Androderm TDDS

- testosterone for 24 hr application

- non-scrotal application: back, abdomen, thighs

- 2.5 or 5 mg

- drug dissolved in alcohol based gel: 12.2 mg for 2.5 mg TDDS

- alcohol, glycerin, glycerol mono-oleate, methyl laurate gelled with acrylic acid copolymer

- reservoir TDDS

Testoderm TDDS types of systems

- non-scrotal application

- scrotum with adhesive

- scrotum without adhesive

nonscrotal application Testoderm

- Testoderm TTS 5mg/day

- reservoir type TDDS

scrotum without adhesive Testoderm

- Testoderm 5 mg or 4 mg/day

- membrane-controlled TDDS

scrotum with adhesive Testoderm

- Testoderm wit adhesive 6 mg/day

- adhesive type TDDS

Fentanyl TDDS

- duragesic 25, 50, 75, and 100 mcg/hr

- only for chronic pain and NOT acute, so there are lag time issues

- opioid analgesic

- not to be used for postoperative analgesia

- used for 72 hr

- contains 0.1 mL alcohol USP per 10 cm^2

- time to attain Tmax is about 30-38 hr

- membrane controlled type reservoir TDDS OLD

- matrix type patch NOW

Ortho-Evra TDDS

- Ortho-McNeil contraceptive patch

- worn 1 week at a time for 3 consecutive weeks

- contains 6 mg norelgestromin and 0.75 mg ethinyl estradiol, releases 150 mcg and 20 mcg resp/24 hrs

- approved by FDA 11/20/01

- 20 cm^2 patch

- middle adhesive layer contains drugs embedded in matrix and a non-woven polyester fabric

amount of transdermal patch products approved in US over past 2 decades

- more than 35

transdermal product prescriptions

- have been used by about 12 million people worldwide for ailments ranging from bladder control to heart disease

marketed products

- Transderm Scop® (scopolamine)

- Duragesic® (fentanyl)

- Transderm-Nitro® (nitroglycerin)

- NicoDerm® CQ® (nicotine)

- Catapres-TTS® (clonidine)

- Testoderm® (testosterone)

- Estraderm® (estradiol)

- Oxytrol® (oxybutynin)

in 2006

- transdermal selegiline Emsam

- somerset pharmaceuticals, Inc.

- for parkinsonism and demetia

2007

- Transdermal Rotigotine (Neupro ®) - Schwartz Pharma for Parkinsonism and Restless Leg Syndrome

- Transdermal Rivastigmine (Exelon ®) - Novartis Pharmaceuticals Corp. For dementia.

- Transdermal Methylphenidate (Daytrana ®) - Shire Pharmaceuticals ADHD-attention deficit disorder

current needs

- patients prefer smaller discrete patches

- patches like to have longer lasting patches

- prefer not to have them visible

- need low irritation from polymer adhesive blends

- need to have no crystallization in patch over time [add polyvinyl pyrrolidone PVP)

the future; examples of recent advances

- novel adhesive polymers: improved wear Evra, a 7-day contraceptive patch

- electronics, miniaturization and skin permeation with electronically assisted GlucoWatch, a glucose monitor for diabetes control

- devices- Bioject and device/patch combinations

DOT Matrix Patch

- Noven Pharmaceuticals

- the acrylic serves only one purpose and it is to hold a lot of drug

- loaded with such high drug concentrations that it would never stick on its own

- it's then added with a silicone adhesive whose only job is to make the patch stick

- marketed small patches such as Vivelle Dot-convenient and effective therapeutically

challenge with skin delivery of larger MW agents

- over 500Da need active not passive delivery approaches

- electrically assisted

- mechanical methods

- miscellaneous

electrically assisted MW agents

- iontophoresis

- electroporation

mechanical MW methods

- microneedles

- abrasion

- needle-less injections

miscellaneous MW agents

- ultrasound, radiofrequency ablation, temperature, laser radiation and photomechanical waves, magnetophoresis

active transdermal delivery

different types of microneedles

- solid

- coated

- dissolving

- hollow

solid microneedles

- silicon

- metal

- polymer

microneedle patches

- currently being explored as mechanisms to deliver vaccines and larger macromolecules

transdermal vaccine technology

- patch delivers vaccine antigen and adjuvant into the stratum corneum

iontophoresis

- a current passed between the active electrode and indifferent electrode repelling drug away from the active electrode and into the skin

electroporation

- also based on the application of a voltage to the skin

- in contrast to iontophoresis where a low voltage os applied, this requires a large voltage treatment for a short period of 10 mcseconds to 100 ms

- produces transient hydrophilic pores across skin barrier, which allow passage of macromolecules via a combination of diffusion, electrophoresis and electroosmosis

principles of electroporation

- short pulses of high voltage current are applied to the skin

- produces hydrophilic pores in the intracellular bilayers via momentary realignment of lipids

sonophoresis/ultrasound examples

- Dermisonics

- U-Strip Transdermal Drug delivery system

- Echo Therapeutics, Inc generation 1.5 and 2.0

more advanced technology becomes...

- more complicated to explain how to use device to administer a medication

thermal methods

- the use of controlled heat allows drugs to permeate the skin more effectively and efficiently than traditional methods

- controlled heat initiates several physiological responses that facilitate drug penetration through the skin

physiological responses that facilitate drug penetration through skin

- increase in skin permeability

- increase in body fluid circulation

- dilation of blood vessels, thus improving permeability through the blood vessel wall

- an improvement in the solubility of most drugs

- increase in the release rate of the drug, from local skin tissue into systemic circulation

Zars Pharma

- thermal method

- control heat-assisted drug delivery CHADD

CHADD

- consists of a powder-filled pouch laminated between a top cover film with oxygen-regulating holes and a bottom film with a pressure-sensitive adhesive layer

- upon contact with oxygen in ambient air, a chemical reaction occurs in the heat-generating medium

- after an initial rise in temperature, the temp generated by the CHADD unit will reach and remain within the controlled temperature range for a pre-determined period of time

- when the heat generating medium is exhausted, the skin temperature gradually returns to baseline

altea therapeutics PassPort system

- single-use disposable PassPort Patch

- Re-usable handheld Applicator

- a conventional transdermal patch attached to an array of metallic filaments 'porator'

how the PassPort system works

- pressing the activation button of the Applicator releases a single pulse of electrical energy to the porator, where it is converted into thermal energy

- the rapid conduction f this thermal energy into the surface of the skin painlessly ablates the stratum corneum under each filament to reate microchannels

- when the applicator is removed, a simple fold-over design aligns the transdermal patch with the newly formed microchannels

Reverse Iontophoresis and Closed Loop Systems

- Animas Johnson and Johnson

- GlucoWatch G2

Crospon and Hewlett Packard

- technology hybrids and micro systems

- one patch contains about 150 microneedles

- enables the drug's dose and time of delivering to be controlled by a microchip

- the patch also contains 400 cylindrical reservoirs

Chrono Therapeutics

- programmable, passive, multidose transdermal systems

- automated and variable delivery profiles

- drug available when it is needed

- improved patient compliance

example of programmable, passive, multidose transdermal systems

- morning dip

- normal lung function undergoes circadian changes and reaches a low point in the early morning hours

substances with proven chrono pharmacological efficiency

- integrated into a miniaturized, automated, programmable watch-like device

user can pre-program the times and amount of each dosage by

- precisely controlling the amount of drug exposed to the skin during each dosing

- device stops diffusion, consequently dosing

other considerations

- manufacturability

- regulatory paths

- insurance coverage

- marketability

manufacturability

- medical device, pharmaceutical or both

- cost

- easy to make, assemble, QA/QC and package

Regulatory paths

- 510K or NDA 505[b][2]

- FDA Office of Combination Products

Marketability

- it is easy for the patient to understand and use

- is it affordable

conclusions

- transdermals are still a multibillion dollar industry and a viable drug delivery platform technology

- key is to cross the stratum corneum and deliver enough flux across the skin

- traditional passive delivery patches are the mainstay of the industry

- novel techniques are constantly being invented and developed for transdermal drug delivery

- almost all are a combination of active and passive skin permeation technologies

the conclusion in red

- transdermal does not necessarily mean a patch system

- can have transdermal gels or invisible patches, like testosterone or nitroglycerin