Exam 3- YOU NEED AN A Flashcards
What is the difference between transdermal and topical application?
Transdermal application is a drug delivery to the systemic circulation through the skin. Topical delivery is delivery on the skin for a local effect.
Is transdermal always a patch?
No it can be gel, ointment, etc.
If it is applied on the skin with a systemic target it is transdermal.
Equilibrium
No net flux or diffusion
Rate of drug delivery same on both sides
Concentration same on both sides
Why does equilibrium not happen in drug delivery?
Because when the drug molecule reaches the other side it gets into the blood which takes it throughout systemic circulation.
Drug stays on left hand side most of the time in topical and transdermal delivery.
Larger surface area=
Higher rate of transport (diffusion)
Increased drug delivery
Definition of flux
J= amount/ SA x time
Rate of transport
Amount transported per unit time
When is flux used over rate of transport?
When you need to compare topical and transdermal formulations if different surface areas are used in different labs during testing.
Flux has SA added to the denominator, it is easier to compare
Is flux dependent on SA?
No, flux is independent of SA
Even though SA is in the equation, flux is not dependent on it.
When the SA changes the amount delivered is doubled so the effect is cancelled out.
If there are two systems, one with a large SA and another with a small SA, which has the higher flux?
The fluxes are the same. Flux is independent of SA
Rate of transport=
J x A
proportional to the area of the membrane
Compare the rate of transport and flux to two transdermal patches one of which is half the size of the other.
Bigger patch compared to smaller one deliver twice the amount of drug however the flux of the patches remains the same
Compare the transport rate and flux of two transdermal patches of the same SA.
One patch has a higher drug concentration than the other.
Rate of transport- Increased with the patch with the higher concentration
Flux- The patch with the higher concentration has a higher flux
Compare the transport rate and flux of two transdermal patches of the same drug concentration.
One patch has a higher SA than the other.
Flux= same
Rate of transport= Higher with a higher SA
Flux is proportional to:
Concentration of the dosage form
J= (constant) x Concentration in dosage form
What is permeability coefficient?
A parameter independent of concentration and surface area P or Kp J=PCd J= (constant) Cd P=D/ h(thickness of membrane)
Flux is normalized by:
Driving force i.e concentration
What is the determining factors of permeability?
Permeability of a membrane like skin is a function of the membrane properties, drug properties, and formulation
What does permeability tell you?
How leaky a membrane is.
Higher permeability= leakier membrane, more permeable
Some useful values of P (permeability)
P= flux normalized by concentration
P for the cornea and buccal is higher
P for the mucosal/monolayer is higher
P is lowest in skin because it functions as a barrier
Flux is inversely proportional to
The thickness of the membrane and r (the permeant molecular radius)
What situation has a higher flux?
Same SA of membrane and same concentration. One side has larger molecules in the concentration
Flux is higher with the smaller molecules
Diffusion coefficient
Proportional to the flux
Related to temperature, viscosity of medium, and molecular size
Relationship of diffusion coefficient with MW of a molecule, viscosity of a medium, temp in a nonaqueous medium
MW- inverse relationship with D
Viscosity- inverse relationship with D
Temp- direct relationship with D
Partition coefficient
The membrane concentration is not the same as the drug concentration.
The higher K (partition coefficient) is the higher drug concentration
Lipophilic drugs have a higher K
Relationship between maximum flux and solubility
Flux is limited by the solubility of a drug
As flux increases it can reach the saturation region Slope between flux and solubiiltiy is P (permeability coefficicent)
You will reach max flux when the solubility is reached
Transdermal delivery requirements
Zeroth order delivery- drug depletion in the patch or in the dosage form
Amount of drug delivered (dose): transdermal flux of a drug!
What is zeroth order delivery?
If you have a concentration/time (y/x axis) for a zero order delivery if you plot the amount delivered across against time then you will see a linear relationship
Flux against time will also be linear relationship
Clearance rate same as absorption
What is 1st order?
See an increase then a decrease
Clearance rate faster than absorption/ delivery rate
Why are most patches assumed or claimed to be zero order?
Because the patch has an infinite supply of drug so you remain a constant concentration.
We try to make transdermal delivery zero order but it is actually first order.
We can remove patch and replace it with new one to remain zero order delivery
GI products vs transdermal
first order because concentration is eliminated over time
We cannot replace GI products like we can transdermal.
Most drugs have >50% absorption
Transdermal systems allow higher % of drugs left in the patch.
What relationship do you use to calculate how long a transdermal patch will last?
Concentration/time= (-P/h)(Cd)
Requirements for slow depletion
Have relatively constant flux for zeroth order drug delivery
(Increase V by increasing A, no effect
Increasing Cp will increase flux)
To make the patch last longer we need to maintain zeroth order delivery so amount delivered or flux are important requirements .
To increase drug delivered per day we can increase
SA and P
Max flux at Cd=
Cs
Why are the doses of commercial transdermal products (patches) proportional to their size (area)?
Manufacturers can just cut out area of a large pass for dose. A higher dose patch will have a higher area
maximum flux
Max drug concentration at solubility
What is the effect on the maximum flux of increasing the solubility by 10 times by the addition of a cosolvent
No effect on the maximum flux
Increasing the solubility (K) will also decrease the drug permeability coefficient cancelling out the effect
The permeability decreases due to the partition coefficient decrease
Even though adding a cosolvent does not affect the flux, what is the benefit?
Increasing duration of transdermal product
What do P and hp (or V at a constant SA) affect in transdermal delivery?
Depletion; for maintaining rate constant of drug delivery, 0th order
Increasing P for drug delivery _______depletion.
Increases
This is why most scientists only look at P instead of depletion
Transdermal delivery, to maintain constant delivery hp can be _________
Increased
However, a thick patch can lead to discomfort and is not patient friendly. Also easier to come off
Transdermal delivery- To increase rate of delivery SA can be _________
increase
But a large patch is not very patient friendly.
Increasing drug concentration in a transdermal patch does not affect______
Depletion because the flux also increases
Drug loading in the patch can be increased by increasing the ________
concentration in the patch without affecting the flux
Cosolvent can increase solubility but does not effect maximum flux
Suspension, emulsion, matrix systems of two or more phases can increase total drug delivery in the system but do not affect concentration that drives drug transport
Can we predict the permeability coefficients of drugs by their physiochemical properties?
Yes
Stratum corneum
Basic barrier of skin
Viable epidermis
Stratus granulosum
Stratum spinosum
Stratum basale
Dermis layers
Papillary and Reticular layers
What layer of skin has the lowest permeability coefficient?
Stratum corneum
Is stratum corneum a rate limiting barrier?
Yes
Why is the stratum corneum the strongest barrier?
Each layer (10-15) has about 5 lamellae between them. It has 60-75 lipid layers of the barrier
Is the stratum corneum thick?
No it is very thin.
10-20 microns
What is the top layer of the stratum corneum?
Stratum disjunctum
Loose desquamated layer of horny cells
How long does it take to regenerate new stratum corneum?
about 2 weeks
What happens if materials penetrate stratum corneum?
They will remain until new stratum corneum is regenerated.
Think of permanent markers not washed off
Stratum granulosum
3-5 layers of flattened cells
Presence of various sized densely packed granular cells
Process of becoming stratum corneum
Stratum spinosum
Several layers of irregular polyhedral cells
Become flattened in outmost layers
Stratum basale
Single row of columnar epithelial cells above the papillae
Growing layer, cells produced in this layer displace the cells above; takes about 30 days to get to the top
Dermis
Generally about 1-2 mm thick
Divided into papillary dermis and reticular dermis
Papillary dermis- outmost part of dermis consisting of connective tissue with collagen, blood capillaries, lymph, and nerves
Reticular dermis- lower and more densely fibered layer. Denser connective tissue and collagenous fibers
Does the epidermis contain any blood?
No
Microneedles
Only go through epidermis an do not touch blood and nerves in dermis. Why they are not painful.
Either a wafer-thin array of microneedles on a patch or drug crystals coated with microneedles
After applying the microneedles to the skin you have to use an activator to provide constant energy, creating hundreds of aqueous channels in the stratum corneum.
Appendages
Hair follicles
Sebaceous glands
Sweat glands
Formed by specialized cells in fetal life; epidermis loses its capacity to generate new hair follicles after birth
Where are skin stem cells?
Hair follicles and stratum basal layer
Sebaceous glands are attached to _______
hair follicle
Hair follicles
Hair is made of slender keratinous filaments and grows in the follicular shaft developed from the epidermal epithelium
Extends down from the tubular opening into the dermis
Inner epithelial component lining of the hair follicle consists of epithelial cells similar to those of the epidermis
Sebaceous glands
Cluster of 2 to 5 alveoli (single layer of cell on alveoli wall) with a single duct
In the dermis with their excretory ducts open into the necks of hair follicles
Filled with fat secretion
No sebaceous glands in palms and soles (no hair)
Sebaceous glands are storage for what?
Sebum
Sweat glands
Simple coiled tubing
Tubes end into a ball as the secretory portion
Sweat glands do not have storage
Greatest number on palms and soles and least in the neck and on back
You have a higher density of hair follicles and sweat glands on the _____________as compared to the trunk and leg
Face, forehead
Why is the density of hair follicles and sweat glands higher on the forehead and face?
Because a person is unable to grow new hair follicles or sweat glands after birth. The face and forehead do not increase SA with growth of the child as much as the other areas of the body.
Stem cell and wound healing
Stem cells are located in stratum basal layer and in the hair follicles
If you have skin damage and the area is small then the area of growing of the basal layer is fast. The stem cells from the basal layer will grow up fast.
Langerhans Cells
Local immune system to process microbial antigens locally in skin infection and travel to T-cell to mature
Melanocytes
Produce melanin, the skin pigment
Skin pigmentation is due to melanocyte activity (lesser to number of melanocytes)
What is suntan a result of?
Damaged DNA triggering the release of a hormone that binds to melanocytes to produce melanin
Where are langerhans and melanocytes located?
The viable epidermis
Corneocytes
Hexagonal in shape, the skin is not flat
Why is the skin not flat?
Due to the corneocytes on the top layer of the stratum corneum
Intracellular pathway
When a drug is put on the surface of the skin it goes inbetween the cells
Major route
Transcellular pathway
Drug goes directly through corneocytes
Stratum corneum intracellular lipids
No phospholipides
Common- Ceramides, cholesterol, fatty acids
Strata basal main lipids
Polar lipids
Strata gransulosum main lipids
Neutral lipids (surface lipids, wax esters, fatty acids, triglycerides, sterols)
Stratum corneum main lipids
Neutral lipids (surface lipids, wax esters, fatty acids, triglycerides, sterols)
and
Ceramides/ sphingolipids
As the strata basal creates new cells, the polar lipids present are converted into what?
Ceramides
Main component of lipids in the skin
Ceramides
In addition of protection, what does the stratum corneum do?
Prevents our own cells from going out
When you put a drug on the skin, what happens?
It goes through stratum corneum and will:
Topical delivery- provide therapeutic effect on the epidermis and dermis
Transdermal- Provide a systemic effect
Metabolism in epidermal and dermal level to remove drug
Advantages of transdermal delivery
Nothing PO pts
Eliminate food effects
Avoid metabolism in GI and hepatic first pass metabolism
Delivery can be terminated with product removal
Pt compliance
Controlled release (zero order input until drug is depleted from patch)
Good for short half-life therapeutic agent
Obstacles and disadvantages of transdermal delivery
Potent drug required
Smaller molecular size of drug
Log Koct around 0-2 (measure of lipophilicity, cannot be too polar or lipophilic)
Permeability coefficient of stratum corneum
Local irritancy and allergy
High local drug concentration (toxicity)
Local first-pass metabolism
Patch can fall off, potential hazard for children, drug can remain in patch and be misused
Cost
What drug potency is required for transdermal delivery?
dose <10mg/day
Potent drug required due to low permeability of stratum corneum
What molecular size is required for transdermal delivery?
<800Da
Toxicity concentration is related to
Dose concentration
How do you avoid a toxic concentration?
Rotate site of administration
Usually stratum basal layer will replace itself
You get a new stratum corneum every _______and a new dermis every _______
2 weeks
month
Why is toxicity due to high amount of drug a problem with transdermal delivery but not delivery to GI tract?
GI tract has a large SA and the local exposure time is short.
Transdermal is always on same tissue
What is tape stripping?
When you put adhesive tape on the skin and peel it off. By peeling it off you get a layer of the stratum corneum pulling off. By continuing to do this you get more stratum corneum pulled off. By measuring this you know the drug concentration in the stratum corneum
Used for topical delivery
Transepidermal water loss (TEWL
Measures barrier properties of skin after topical drug administration
Evaporimeter, vapometer placed on the skin
Passive diffusion of water, water is leaving surface.
Mainly for evaluation of barrier disruption and repair
Side-by-side diffusion cells
Two sides. You put the drug concentration on one side and the receiver solution on the other. Circulating temp control center.
Basic studies
Vertical Franz diffusion cells
Top is formulation, middle skin, bottom chamber
Put formulation in top that is exposed to atmosphere
Done for formulation testing and screening as well as quality control
More common than side by side
Measure amount that reaches bottom chamber
Slope of plot is flux value
In formulation and transdermal system testing, what skin is used?
Human skin
- cadaver
- skin from surgery
Expensive
Preferred in vivo testing, but expensive and time consuming
Animal skin commonly used (hairless rats and mice have hair follicles still)
Is the stratum corneum thickness the same between different species?
No
Only pig skin is a good model for human skin
Whole skin thickness difference is different as well
You have to correct for______when testing transdermal products in mice
Body size
Are rodents good models for transdermal products?
no
Back, abdomen, arm, thigh permeability
Comparable
Face, scalp, genitalia permeability
High
Palmar/plantar (sole)
Thick, but high water permeability
Water hydration can_______permeation
Enhance
Soaking your hand in water swells the stratum corneum
Normal rate of passive diffusion of water through skin
4-15g/m^2/hr
Skin transport model: lipophilic drugs go through what?
Pore pathway and lipid pathway
Skin transport model: hydrophilic drugs go through what?
Pore pathway
Maximum flux is independent of cosolvent system
T/F
True
Butrans
Pain management
Cannot take oral due to N
Catapres
7 day delivery system for HTN
Reservoir patch
Traditional
Backinf, drug reservoir, control membrane, protective peel strip
Cannot cut
Androderm system
reservoir patch
You will see a drug resorvoir
Selegiline (emsam)
Adhesive patch
What is the difference in an adhesive patch and matrix patch?
An adhesive patch has drug in the adhesive a matrix patch has drug in the matric
1st gen of transdermal delivery
Reservoir patch
Daytrana
matrix patch
Apply for only 9 hours
Systemic half life of drug is 2-3 hours
Adhesive patches are easier to make T/F
T
Problem with adhesive patch
Potential problem of drug and excipients interacting with adhesive
Selegiline (Emsam)
Adhesive patch
Estrogel
Transdermal estradiol gel
Once daily application of 2.5g (each arm, wrist to shoulder (750cm^2 skin area))
Dries in 2 to 5 minutes
Testim, Androgel, Vogelxo
1% transdermal testosterone gel
Once daily administration
About 10% of applied dose is absorbed over 24 hours
Estrasorb
2.5mg estradiol/g emulsion micellar transdermal system
Once daily application of 2 foil packages, rub on thigh or calf
Provides 0.05mg/day
Disadvantages of EstroGel
Applying to large SA
Remains on skin for 2-5 minutes
Transdermal spray
Testosterone and estradiol metered dose transdermal spray
Luramist testosterone and EvaMist estradiol
MDTS places against the skin to release a spray that dries quickly (need a 2 minute wait before dressing and 30 minute wait before washing.
Forms a drug depot
Once daily administration
Less AE than patches
Fentanyl systems
9 different transdermal products
Pts need to be careful with size of patches
Transdermal products are usually new active ingredients T/F
F
They are usually made out of existing drugs
Free medium
What is touching the skin
Methods for enhancing skin transport
Physical enhancers (for controlled delivery of larger and less lipophilic drugs) Iontophoresis Sonophoresis High electrical field electroporation Punctuation and mechanical methods heat Chemical enhancers
Iontophoresis
The enhances transport of a drug across a biomembrane under the assistance of an electric field.
the movement of a charged molecule
Apply positive polarity
Problems with iontophoresis
Unwanted skin rxns at current >0.5mA/cm^2 and long tx: edema, erythema, irritation, contact dermatitis, sunburn
Electrochemical products at the electrode surface can affect skin (pH or silver burn)
Sensation
Power supply
Flux variability
Iomed: lidocaine
Iontophoresis
For topical, not transdermal delivery
Why is epinephrine used in combination with lidocaine for local topical delivery?
Epi is a vasoconstrictor so it enhances duration of the lidocaine numbing effect to the skin
Epi also reduces skin clearance at the local site
Iontophoresis: You put positively charged drugs in the ________side
Positive
Iontophoresis- what can you deliver?
Methylene phosphates (dexamethasone) or local numbing (lidocaine)
Two main advantages of iontophoresis compared to oil:
Quick onset of action (reduce onset time)
Enhance penetration
Ionsys
Needle free, patient friendly
Iontophoresis Fentanyl
Button for breakthrough pain- push it and it goes transdermally. Applies electric current to enhance delivery
Glucowatch problems
Permeability- not accurate
Can say normal when pt is actually hypoglycemic
Sonophoresis
The enhancement of a drug/compound transport across a biomembrane under the assistance of ultrasound
Mech of enhancement: Pore induction (membrane alteration due to cavitation, convection, stratum corneum lipid modification)
Sontra medical
Apply ultrasound then cream
Ultrasound to the skin for a period of seconds to create reversible microchannels through stratum corneum
Used for rapid anesthesia in 5 minutes from 4% lidocaine
Transdermal glucose and vaccine under development
Potential problems with sonophoresis
Heat Feasibility (enhancers like SDS are needed) Variability of energy Unpredictable flux Skin to skin variability
Electroporation
The enhanced transport of a drug/compound across a biomembrane under the assistance of high electric field short pulses
Similar to static sparks
Mech of enhancement are similar to those of iontophoresis with a major contribution from electropermeabilization (membrane alteration, pore induction)
Potential problems with electroporation
Similar concerns to iontophoresis
In addition- sensation, tissue damage, muscle reflux and reaction
How do you reduce current across the muscle with electroporation?
Microarray electrodes
Helps decrease current from reaching the muscle
Or pull skin away from body surface
Microneedles
Physically punctuate the stratum corneum to create micropores
Water-soluble drugs and macromolecules
No pain
4 types of microneedles
Solid-permeabilizing skin and drug patch
Solid coated with drug or vaccine
Dissolvable polymeric microneedles encapsulated drug or vaccine
Hollow for injection of drug solution
Microporation: heat
Create a pore across the stratum corneum by heat
Melts stratum corneum lipids to create pores
In trial for insulin, pain, and GLP agonists
Increases permeability, rate, and transdermal delivery
Physical enhancers are more useful for
Polar, ionic, macromolecules
Chemical enhancers are more useful for
Moderately lipophilic, normal small molecule drug
Low energy heat
Increase skin permeability
-Skin structural changes
Increases rate of release of the drug from local skin tissue into systemic circulation
Increases body circulation
Improves solubility of most drugs
Most transdermal patches have a warning to avoid heat because______
it can lead to overdose
Heat can significantly ________the delivery rates or penetration of the drug through the skin into systemic circulation
Increase
FDA approvals of medical devices
Premarket approval application (PMA)- new or high-risk medical devices that require a more rigorous premarket review than the 510(k) pathway. PMA is similar to NDA but is used for medical devices
510 (k) clearances
New devices that are substantially equivalent to a device that is already legally marketed for the same use
Investigational device exemption (IDE)
Investigational device to be used in a clinical study to collect safety and efficacy data
Chemical enhancers
Adding an inactive ingredient to transdermal products to increase the penetration to the skin Sulfoxides Alcohols- long chain fatty alcohol Fatty acids Fatty acid esters Surfactants
What is the most common chemical enhancer? For enhancing penetration of drug throughout the skin
Fatty acid esters
Isopropyl palmitate
Mechanisms of chemical permeation enhancers
Fludization of the intercellular lipid lamellae of the stratum corneum
Alteration of the chemical microenvironment in the intercellular lipid lamellae (solvent penetrates and increases the solubility of drug in skin)
Lipid extraction
Enhance the penetration of permeation enhancers
Considerations for effective permeation enhancement
Physiochemical properties of the drug
-polar or lipohilic?
Concentration of enhancer and nature of mechanism (target of enhancers is lipids not target of drug)
Depletion of vehicle and enhancers due to evaporation of skin penetration
Nature/mechanism of the permeation enhancer
Properties of good chemical enhancers
Significant flux enhancement Pharmacologically inert Nonirritating, nonallergenic, nontoxic, Rapid onset of action and long duration Reversible effect Compatible, both chemically and physically Odorless, colorless, inexpensive Cosmetically acceptable
Topical delivery
Target site: epidermis or dermis
Less amount required to be delivered vs transdermal
Topical delivery: drugs need to be
Not too large in MW
Not too hydrophilic
Not skin irritant or allergy
Types of topical products
Medicated- contains therapeutic agents, dissolved or suspended.
Nonmedicated- protectants or lubricants
Medical indication- drug regulated by FDA
Topical dosage forms
Solution, suspension, lotion, ointment, cream, gel, paste
Topical semisolids
Melting point and solid state at room temperature
Ointment, cream, gel, paste
Topical aerosol or non-aerosol pump foams
Liquid in storage, foams when dispensing
Epidermic base
None or very little skin permeation
Oleaginous base
Epidermic refers to external layer of the skin or epidermis
Endodermic base
Into dermis skin permeation
Absorption base
Endodermic refers to internal layer of the skin or epidermis
Diadermic base
Into and through skin permeation
Emulsion, water soluble base
Diadermic refers to going through the skin
Oleaginous base
Insoluble in water, will not absorb water Emollient Greasy Occlusive White petrolatum and white ointment
Absorption base
Insoluble in water, will absorb water Emollient Occlusive Anhydrous Greasy Hydophilic petrolatum, aquabase, aquaphor, polysorbate
Emulsion; water in oil
Insoluble in water, will absorb water Contains water Emollient Greasy Occlusive Cold cream, lanolin, hydrocream, eucerin, nivea
Emulsion; oil in water
Insoluble in water, will absorb water Water washable Contains water Nonocclusive Nongreasy Hydrophilic ointment, unibase, velvachol, dermabase
Water soluble base
Water soluble, washable Will absorb water Anhydrous or hydrous Nonocclusive Nongreasy Lipid-free Polyethylene glycol ointment
Creams
Dissolved or dispersed in emulsions (oil-in-water) or water-washable base
Semisolid
Creamy white appearance
Easier to spread and remove than ointments
Gels
Dispersions in an aqueous jelly-like liquid vehicle (normally water) with a gelling agent
Can be considered either a single-phase or 2 phase
Gel of macromolecules
May be formulated with cosolvent such as alcohol and propylene glycol
Paste
Contains larger proportion of solid materials (insoluble solids) than ointments
Stiffer
Less base used: Less greasy than ointments
Zinc oxide paste
Problems with topical dosage form classification
Not consistent, none are official Not quantitative, based on opinion Can overlap (non exclusive)
FDA approved bioequivalence test
Vasoconstrictor assay for topical corticosteroids (look at blanching of skin (change in color))
Case by case basis-
Absorption studies using tape stripping
Absorption studies using skin biopsy
PK studies (systemic) if a significant amount of a drug is absorbed into systemic circulation- apply drug on skin and measure plasma conc.
Diffusion cells- transport experiments (drug in formulation in donor and receiver measured)
Transepidermal water loss (TEWL)
Microdialysis (tubing in skin)
Bioequivalence
No significant difference in the rate and extent to which an active ingredient becoming available at the site of drug action when administered
Cmax and AUC same
Purpose: to establish therapeutic equivalence so physicians can treat patients with the alternative medication without further monitoring
The rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient.
Requirements of BE
90% confidence interval must fall between:
Dichotomized +/- 0.2 of the innovator
Numerical- 80%-125% of the innovator
Superior to placebo demonstrated
Q1,Q2,Q3 for BE
Generic equivalent to get approved without clinical trials
When two products are Q1, Q2, and Q3 equivalent they are considered to be BE
Q1- same components
Q2- same components in same concentration
Q3- same components in same concentration and same microstructure
Zecuity
Sumatriptan succinate
Iontophoretic transdermal system (TDS)
Caused skin irritation, no longer on market
LidoSite (Vyteris)
Pre-filled iontophoresis system of lidocaine/ epi
Treatment of migraine
Wet
Needle free
Relationship between fentanyl delivery and electric current
Linear
Lipid membrane electroporation
Spontaneous formation of metastable pore due to energy in electric field
Minimum voltage- around 0.2-1.0 V per bilayer, depending on bilayer composition. Need about 50V based on the number of bilayers.
Microporation lasers
Creates pore with laser
P.L.E.A.S.E system
Chrono therapeutics
Iontophoresis system
Delivers acyclovir to local skin area
Delivers steroids locally to treat acne and psoriasis
SmartStop- for smokers to deliver nicotine during cravings
What are microneedles used to deliver?
Water-soluble drugs and macromolecules
Alza macroflux microneedle system
Desmopressin- hormone found naturally in the body for increasing urine concentration and decreasing urine production
Rapidly dissolving microneedles
Dissolve in 60 minutes
3M Microneedle system
polyclonal antibody delivery
Microporation: RF-wave
Radiofrequency (RF) to porate skin similar to radiofrequency scalpel
Creates RF- microchannels
GLP-1 agonist and osteoporosis
PassPort system
Single-use disposable patch with a re-useable applicator with an array of metallic filaments. Converts electrical energy/pulse to thermal energy that ablates the stratum corneum to create microchannels. The patch is then placed on the skin.
A type of heat microporation.
Abrasive pads (sandpaper device) to enhance transdermal delivery
TEWL and efficacy of transdermal application were found to increase after treatment
ZARS
Controlled heat assisted drug delivery (CHADD) system
Fentanyl
What topical dosage form is not a liquid
Aerosol
Powder
Patch
What dosage form is a clear and homogenous liquid?
Solutions
What dosage form is a solid dispersed liquid?
Suspension
What dosage form is an emulsion?
Lotion
What dosage form is a semisolid that contains >50% LOD and is a solution or colloidal dispersion?
Gel
What dosage form is a semisolid contains >50% LOD an is an emulsion?
Cream
What dosage form is a semisolid that contains a large proportion (20-50%) of dispersed solids?
Paste
What dosage form is a semisolid that contains >50% of hydrocarbons, waxes. or PEG and <20% LOD?
Ointment
Evaluation of topical systems that have been FDA approved or considered
Controlled clinical trials to test efficacy against disease (for new and generic products)
For generic products- tests to establish bioequivalence
Therapeutic equivalent
Have the same clinical effect and safety profile when administered to patients under the conditions specified in labeling
It is an FDA term used for the evaluation of generic drugs. It is used to answer the question: are the generic and innovator products the same for all intents and purposes? Do they show the same performance?
When are products considered to be therapeutic equivalent?
Pharmaceutical equivalent and bioequivalent
Safe and effective
Adequately labeled and manufactured in compliance with good manufacturing practice
Pharmaceutical equivalent and bioequivalent are the two key components
Pharmaceutical equivalents
Contain identical amounts of the same active drug ingredient in the same dosage form and route of administration
and
meet compendial or other applicable standards of strength, quality, purity, and identity
Current practice of equivalence
Pharmaceutical equivalence + Bioequivalence= Therapeutic equivalence
BE tests
Actives in biological fluid in patients (plasma)
PD comparison (Check BP for HTN/ cholesterol for cholesterol meds)
Clinical comparisons (clinical endpoints, cure of disease/remission)
Other in vitro tests deemed adequate by FDA
BE for local delivery
Different than the BE for systemic (bioavailability)
Small sample mass (eye, ear wax, etc)
Samples may not be easy to reach
Poor systemic absorption, intended for local delivery
Examples- inhalation, topical, eye, locally acting GI products
Q3 identical products are ________
bioequivalent
Ex- topical solutions
Direct demonstration for Q3 equivalence is difficult in ______
formulations more complex than solutions
Ex.- creams, ointments, gels
Q1 and Q2 are identical
There may be differences in Q3 due to manufacturing process
Requires additional evaluations of rheology, in vitro release (diffusion) and in vitro tests
Differences in Q1 and Q2
May be required because of formulation patents
When products differ in Q1 and Q2 additional tests are required for BE
Dosage for classification is uncertain which may be a barrier for generic evaluation
Active ingredient
Any component of a drug product intended to furnish pharmacological activity or other direct effect in the diagnosis, prevention, cure
Inactive ingredient (excipients)
Any component of a drug other than the active ingredient.
Ingredients that physically or chemically combine with an active ingredient to facilitate drug transport
Can be considered active under different circumstances (alcohol)
Oral powder and granules
Direct use- dissolved in solution
Traditional, simple
Used for large doses that cannot be administered as a tablet or a capsule
Oral tablets
SImple compressed tablet (uncoated)
Coated- coated by sugar, film, or enteric
Chewable- rapid disintegration when chewed
Direct commpression
Tablets are prepared by direct compression of a drug powder mixed with other excipients
Oral capsule
Gelatin or hypromellose capsule
Hard shell capsule- filled with powder, granulate, paste
Soft gel capsule- gelatin with glycerin or polyhydric alcohol usually filled with oil
Gelatin
Protein
Obtained by hydrolysis of collagen from skin, white connective tissue, and bones of animals
Soluble in warm water and digested by enzymes and absorbed
Stable
Types of excipients
Fillers (diluents), binders, disintegrants, lubricants, glidants, antiadherents, colors, flavors, sweeteners
Diluents
Added to increase bulk of preparation
Must be compatible with drugs
Water-soluble diluents are recommended for use with drugs that have low water solubility to avoid precipitation
Binders
Increase cohesive qualities of powdered materials
Ensure that the tablet will remain intact after compression
Too much or too strong a binder can delay tablet disintegration
More effective if used in wet rather than dispersed in dry form
Microcrystalline cellulose
Excipient
Diluent and binder
Lubricants
Reduce friction at the interface of tablet and die wall during compression and ejection
PEG 4000, magnesium
Antiadherents
Prevent sticking to the punch and to the die wall
talc, magnesium stearate
Glidants
Improve flow characteristics of granulate
corn starch, amorphous silica
Magnesium lauryl sulfate
Used as a tablet or capsule lubricant (wetting agent)
Functions as an anionic surfactant, detergent, emulsifying agent
Incompatible with cationic surfactants and salts of polyvalent metal ions (zine, aluminum, tin, lead)
Widely used, safe
Disintegrants
Facilitates tablet breakup after administration, hence improve dissolution
cross-linked cellulose
Colorants
appearance appeal and identification
How to find excipients?
The FDA has a database
Inactive Ingredient Search for Approved Drug Products
GRAS
Generally recognized as safe
Commonly used as excipients
Chemical bulk ingredients
USP NF FCC COA Chemically pure, analytical reagent grade before printed expiration date when stored in original container
Quality testing
Manufacturer is required to demonstrate to the FDA that each dosage unit in a batch has a drug content within the range on the label
Uniformity of dosage unit- demonstrated by content uniformity or weight variation
Not applied to suspensions, emulsions, or gels in unit-dose container intended for external administration
Content uniformity test
An assay of the individual content of drug substance in a number of dosage units to determine whether the individual content is within the limits set
Mostly destructive and consumes the drug using wet chemical analysis
Weight variation test
An assay of the drug substance based on weight
USP 905 uniformity of dosage unit
The uniformity of dosage units can be demonstrated by either content uniformity or weight variation
The orange book
Approved drugs with therapeutic equivalence both OTC and Rx
Cumulative
FDA resource
Iontophoresis current
Less than 0.5mA/cm^2
Very small electric current
Unwanted skin reactions occur when current >0.5mA/cm^2
When you apply an electric field across the skin, the electrical resistance of the skin _________
Decreases to about 1-2kOms/cm
The electrical resistance is usually high (100kOm/cm)
This is why we get shocked
Companion 80 and Hybresis
Iontophoresis
Has batteries
WEDD
Iontophoresis
No batteries
Utilize different metals in the electrodes
Potato example
Cannot control voltage as well but is more patient friendly
Lidocaine is _______charged and methylene phosphate is ______ charged
Positively
Negatively
What is the advantage of the dry iontophoresis
You can use a drug off label (dexamethasone)
Do not have to get approved by FDA
2 main advantages for transdermal delivery (iontophoresis)
Reduce onset time
Increase penetration
What is the main advantage of wet iontophoresis
Electrode may reduce stability of drug in storage with dry delivery.
This is not an issue with wet.
What is more effective, ITS or PCA?
comparable
In addition to delivering a drug to the body, what can iontophoresis do?
Extract materials from the body
Think glucose monitoring system
What is the main difference between ultrasound for diagnosis and sonophoresis?
Power- much higher power to break down the skin in sonophoresis
Frequency- Diagnosis ultrasound is very high and sonophoresis is low
Does iontophoresis or electroporation increase delivery more?
Iontophoresis
highest delivery is combination of the 2
Which microneedle system injects the drug?
Hollow
What are the methods to put wholes in the corneum?
Heat
Microneedles
Lasers
RF
Physical enhancers are more useful for
Polar, ionic, macromolecules
Heat can significantly increase
Delivery rates and penetration of drug in transdermal delivery
Can lead to OD
How much can the stratum corneum swell?
3x
Does having the same Cmax and AUC indicate that you have the same concentration in the skin tissue?
No
Topical BE cannot be assessed by _______-
Blood circulation
You can have different tissue and plasma concentrations
What are you measuring with in vitro diffusion cell with full thickness skin
Full skin assay
What are you measuring with systemic PK and skin biopsy
To the dermis
What are you measuring with TEWL
Through the viable epidermis
What are you measuring with Tape- stripping
SC
What is the purpose of Q1,Q2, and Q3?
To not have clinical trials to establish BE
Q3 equivalence is needed for what?
Creams oitments
Semisolids
Q2 is considered BE for what?
Solutions
Dibasic calcium phosphate dehydrate
Diluent
Lactose, calcium sulfate dehydrate
diluent
microcrystalline cellulose, starch
diluent
sucrose based diluents, mannitol NaCl
diluent
cellular derivatives
binder
PEG, starch paste, synthetic gums
binder
If you have a small dose of a drug you will see
diluents, fillers
If you have a large dose of a drug you will see
Binders
PEG 4000, magnesium or Na lauryl sulfate, stearic acid
lubricants
talc, magnesium stearate
Antiadherents
Corn starch, amorphous silica
Glidants
cross-linked cellulose, cross-linked polyvinyl pyrrolidone, modified corn starch
disintegrants
iron oxide, titanium oxide
colorants
Advil inactive ingredients: silicon dioxide corn starch croscarmellose microcrystalline cellulose sodium lauryl sulfate and steric acid titanium dioxide parabens and sodium benzoate
silicon dioxide- glidant
corn starch- glidant
croscarmellose- disintegrant
microcrystalline cellulose- binder
sodium lauryl sulfate and steric acid- lubricant/antiadherent
titanium dioxide- colorant
parabens and sodium benzoate- preservatives
DILAUDID inactive ingredients lactose anhydrous magnesium stearate d&C dyes sodium metabisulfite
lactose anhydrous- diluent
magnesium stearate- lubricant
d&C dyes- colorant
sodium metabisulfite- preservative
Tetracycline hydrochloride inactive ingredients Gelatin and propylene glycol Pregelatinized starch Sodium dioxide Stearic acid Titanium dioxide D&C and DD&C dyes
Gelatin and propylene glycol- capsule Pregelatinized starch- diluent Sodium dioxide- glidant Stearic acid- lubricant Titanium dioxide- colorant D&C and DD&C dyes- colorant
Are there any binders in capsules?
No
Pennsaid, diclofenac 2% inactive ingredients dimethyl sulfoxide ethanol water propylene glycol hydroxypropyl cellulose
dimethyl sulfoxide- solvent
ethanol- solvent
water- solvent
propylene glycol- polymer to increase viscosity
hydroxypropyl cellulose- polymer to increase viscosity
Most inactive ingredients in patches are
adhesives
Porous microsphere
Put in gels to capture the lipophilic drugs. Needed because of poor aqueous solubility.
Methyl methacrylate/glycol
Why are polymers added to gels?
To increase viscosity
Carbomer 940
Polymer in gel
hydroxypropyl cellulose
Polymer in increase viscosity
If an inactive ingredient is in the GRAS database no additional tests need to be conducted before use T/F
T
WV means
You can use weight variation or content verification
