Exam 3- YOU NEED AN A Flashcards
1
Q
What is the difference between transdermal and topical application?
A
Transdermal application is a drug delivery to the systemic circulation through the skin. Topical delivery is delivery on the skin for a local effect.
2
Q
Is transdermal always a patch?
A
No it can be gel, ointment, etc.
If it is applied on the skin with a systemic target it is transdermal.
3
Q
Equilibrium
A
No net flux or diffusion
Rate of drug delivery same on both sides
Concentration same on both sides
4
Q
Why does equilibrium not happen in drug delivery?
A
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.
5
Q
Larger surface area=
A
Higher rate of transport (diffusion)
Increased drug delivery
6
Q
Definition of flux
A
J= amount/ SA x time
7
Q
Rate of transport
A
Amount transported per unit time
8
Q
When is flux used over rate of transport?
A
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
9
Q
Is flux dependent on SA?
A
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.
10
Q
If there are two systems, one with a large SA and another with a small SA, which has the higher flux?
A
The fluxes are the same. Flux is independent of SA
11
Q
Rate of transport=
A
J x A
proportional to the area of the membrane
12
Q
Compare the rate of transport and flux to two transdermal patches one of which is half the size of the other.
A
Bigger patch compared to smaller one deliver twice the amount of drug however the flux of the patches remains the same
13
Q
Compare the transport rate and flux of two transdermal patches of the same SA.
One patch has a higher drug concentration than the other.
A
Rate of transport- Increased with the patch with the higher concentration
Flux- The patch with the higher concentration has a higher flux
14
Q
Compare the transport rate and flux of two transdermal patches of the same drug concentration.
One patch has a higher SA than the other.
A
Flux= same
Rate of transport= Higher with a higher SA
15
Q
Flux is proportional to:
A
Concentration of the dosage form
J= (constant) x Concentration in dosage form
16
Q
What is permeability coefficient?
A
A parameter independent of concentration and surface area P or Kp J=PCd J= (constant) Cd P=D/ h(thickness of membrane)
17
Q
Flux is normalized by:
A
Driving force i.e concentration
18
Q
What is the determining factors of permeability?
A
Permeability of a membrane like skin is a function of the membrane properties, drug properties, and formulation
19
Q
What does permeability tell you?
A
How leaky a membrane is.
Higher permeability= leakier membrane, more permeable
20
Q
Some useful values of P (permeability)
A
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
21
Q
Flux is inversely proportional to
A
The thickness of the membrane and r (the permeant molecular radius)
22
Q
What situation has a higher flux?
Same SA of membrane and same concentration. One side has larger molecules in the concentration
A
Flux is higher with the smaller molecules
23
Q
Diffusion coefficient
A
Proportional to the flux
Related to temperature, viscosity of medium, and molecular size
24
Q
Relationship of diffusion coefficient with MW of a molecule, viscosity of a medium, temp in a nonaqueous medium
A
MW- inverse relationship with D
Viscosity- inverse relationship with D
Temp- direct relationship with D
25
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
26
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
27
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!
28
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
29
What is 1st order?
See an increase then a decrease
| Clearance rate faster than absorption/ delivery rate
30
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
31
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.
32
What relationship do you use to calculate how long a transdermal patch will last?
Concentration/time= (-P/h)(Cd)
33
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 .
34
To increase drug delivered per day we can increase
SA and P
35
Max flux at Cd=
Cs
36
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
37
maximum flux
Max drug concentration at solubility
38
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
39
Even though adding a cosolvent does not affect the flux, what is the benefit?
Increasing duration of transdermal product
40
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
41
Increasing P for drug delivery _______depletion.
Increases
| This is why most scientists only look at P instead of depletion
42
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
43
Transdermal delivery- To increase rate of delivery SA can be _________
increase
| But a large patch is not very patient friendly.
44
Increasing drug concentration in a transdermal patch does not affect______
Depletion because the flux also increases
45
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
46
Can we predict the permeability coefficients of drugs by their physiochemical properties?
Yes
47
Stratum corneum
Basic barrier of skin
48
Viable epidermis
Stratus granulosum
Stratum spinosum
Stratum basale
49
Dermis layers
Papillary and Reticular layers
50
What layer of skin has the lowest permeability coefficient?
Stratum corneum
51
Is stratum corneum a rate limiting barrier?
Yes
52
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
53
Is the stratum corneum thick?
No it is very thin.
| 10-20 microns
54
What is the top layer of the stratum corneum?
Stratum disjunctum
| Loose desquamated layer of horny cells
55
How long does it take to regenerate new stratum corneum?
about 2 weeks
56
What happens if materials penetrate stratum corneum?
They will remain until new stratum corneum is regenerated.
| Think of permanent markers not washed off
57
Stratum granulosum
3-5 layers of flattened cells
Presence of various sized densely packed granular cells
Process of becoming stratum corneum
58
Stratum spinosum
Several layers of irregular polyhedral cells
| Become flattened in outmost layers
59
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
60
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
61
Does the epidermis contain any blood?
No
62
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.
63
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
64
Where are skin stem cells?
Hair follicles and stratum basal layer
65
Sebaceous glands are attached to _______
hair follicle
66
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
67
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)
68
Sebaceous glands are storage for what?
Sebum
69
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
70
You have a higher density of hair follicles and sweat glands on the _____________as compared to the trunk and leg
Face, forehead
71
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.
72
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.
73
Langerhans Cells
Local immune system to process microbial antigens locally in skin infection and travel to T-cell to mature
74
Melanocytes
Produce melanin, the skin pigment
| Skin pigmentation is due to melanocyte activity (lesser to number of melanocytes)
75
What is suntan a result of?
Damaged DNA triggering the release of a hormone that binds to melanocytes to produce melanin
76
Where are langerhans and melanocytes located?
The viable epidermis
77
Corneocytes
Hexagonal in shape, the skin is not flat
78
Why is the skin not flat?
Due to the corneocytes on the top layer of the stratum corneum
79
Intracellular pathway
When a drug is put on the surface of the skin it goes inbetween the cells
Major route
80
Transcellular pathway
Drug goes directly through corneocytes
81
Stratum corneum intracellular lipids
No phospholipides
| Common- Ceramides, cholesterol, fatty acids
82
Strata basal main lipids
Polar lipids
83
Strata gransulosum main lipids
Neutral lipids (surface lipids, wax esters, fatty acids, triglycerides, sterols)
84
Stratum corneum main lipids
Neutral lipids (surface lipids, wax esters, fatty acids, triglycerides, sterols)
and
Ceramides/ sphingolipids
85
As the strata basal creates new cells, the polar lipids present are converted into what?
Ceramides
86
Main component of lipids in the skin
Ceramides
87
In addition of protection, what does the stratum corneum do?
Prevents our own cells from going out
88
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
89
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
90
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
91
What drug potency is required for transdermal delivery?
dose <10mg/day
| Potent drug required due to low permeability of stratum corneum
92
What molecular size is required for transdermal delivery?
<800Da
93
Toxicity concentration is related to
Dose concentration
94
How do you avoid a toxic concentration?
Rotate site of administration
| Usually stratum basal layer will replace itself
95
You get a new stratum corneum every _______and a new dermis every _______
2 weeks
| month
96
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
97
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
98
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
99
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
100
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
101
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)
102
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
103
You have to correct for______when testing transdermal products in mice
Body size
104
Are rodents good models for transdermal products?
no
105
Back, abdomen, arm, thigh permeability
Comparable
106
Face, scalp, genitalia permeability
High
107
Palmar/plantar (sole)
Thick, but high water permeability
108
Water hydration can_______permeation
Enhance
Soaking your hand in water swells the stratum corneum
109
Normal rate of passive diffusion of water through skin
4-15g/m^2/hr
110
Skin transport model: lipophilic drugs go through what?
Pore pathway and lipid pathway
111
Skin transport model: hydrophilic drugs go through what?
Pore pathway
112
Maximum flux is independent of cosolvent system
| T/F
True
113
Butrans
Pain management
| Cannot take oral due to N
114
Catapres
7 day delivery system for HTN
115
Reservoir patch
Traditional
Backinf, drug reservoir, control membrane, protective peel strip
Cannot cut
116
Androderm system
reservoir patch
| You will see a drug resorvoir
117
Selegiline (emsam)
Adhesive patch
118
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
119
1st gen of transdermal delivery
Reservoir patch
120
Daytrana
matrix patch
Apply for only 9 hours
Systemic half life of drug is 2-3 hours
121
Adhesive patches are easier to make T/F
T
122
Problem with adhesive patch
Potential problem of drug and excipients interacting with adhesive
123
Selegiline (Emsam)
Adhesive patch
124
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
125
Testim, Androgel, Vogelxo
1% transdermal testosterone gel
Once daily administration
About 10% of applied dose is absorbed over 24 hours
126
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
127
Disadvantages of EstroGel
Applying to large SA
| Remains on skin for 2-5 minutes
128
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
129
Fentanyl systems
9 different transdermal products
| Pts need to be careful with size of patches
130
Transdermal products are usually new active ingredients T/F
F
| They are usually made out of existing drugs
131
Free medium
What is touching the skin
132
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
```
133
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
134
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
135
Iomed: lidocaine
Iontophoresis
| For topical, not transdermal delivery
136
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
137
Iontophoresis: You put positively charged drugs in the ________side
Positive
138
Iontophoresis- what can you deliver?
```
Methylene phosphates (dexamethasone)
or local numbing (lidocaine)
```
139
Two main advantages of iontophoresis compared to oil:
Quick onset of action (reduce onset time)
| Enhance penetration
140
Ionsys
Needle free, patient friendly
Iontophoresis Fentanyl
Button for breakthrough pain- push it and it goes transdermally. Applies electric current to enhance delivery
141
Glucowatch problems
Permeability- not accurate
| Can say normal when pt is actually hypoglycemic
142
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)
143
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
144
Potential problems with sonophoresis
```
Heat
Feasibility (enhancers like SDS are needed)
Variability of energy
Unpredictable flux
Skin to skin variability
```
145
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)
146
Potential problems with electroporation
Similar concerns to iontophoresis
| In addition- sensation, tissue damage, muscle reflux and reaction
147
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
148
Microneedles
Physically punctuate the stratum corneum to create micropores
Water-soluble drugs and macromolecules
No pain
149
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
150
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
151
Physical enhancers are more useful for
Polar, ionic, macromolecules
152
Chemical enhancers are more useful for
Moderately lipophilic, normal small molecule drug
153
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
154
Most transdermal patches have a warning to avoid heat because______
it can lead to overdose
155
Heat can significantly ________the delivery rates or penetration of the drug through the skin into systemic circulation
Increase
156
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
157
510 (k) clearances
New devices that are substantially equivalent to a device that is already legally marketed for the same use
158
Investigational device exemption (IDE)
Investigational device to be used in a clinical study to collect safety and efficacy data
159
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
```
160
What is the most common chemical enhancer? For enhancing penetration of drug throughout the skin
Fatty acid esters
| Isopropyl palmitate
161
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
162
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
163
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
```
164
Topical delivery
Target site: epidermis or dermis
| Less amount required to be delivered vs transdermal
165
Topical delivery: drugs need to be
Not too large in MW
Not too hydrophilic
Not skin irritant or allergy
166
Types of topical products
Medicated- contains therapeutic agents, dissolved or suspended.
Nonmedicated- protectants or lubricants
Medical indication- drug regulated by FDA
167
Topical dosage forms
Solution, suspension, lotion, ointment, cream, gel, paste
168
Topical semisolids
Melting point and solid state at room temperature
| Ointment, cream, gel, paste
169
Topical aerosol or non-aerosol pump foams
Liquid in storage, foams when dispensing
170
Epidermic base
None or very little skin permeation
Oleaginous base
Epidermic refers to external layer of the skin or epidermis
171
Endodermic base
Into dermis skin permeation
Absorption base
Endodermic refers to internal layer of the skin or epidermis
172
Diadermic base
Into and through skin permeation
Emulsion, water soluble base
Diadermic refers to going through the skin
173
Oleaginous base
```
Insoluble in water, will not absorb water
Emollient
Greasy
Occlusive
White petrolatum and white ointment
```
174
Absorption base
```
Insoluble in water, will absorb water
Emollient
Occlusive
Anhydrous
Greasy
Hydophilic petrolatum, aquabase, aquaphor, polysorbate
```
175
Emulsion; water in oil
```
Insoluble in water, will absorb water
Contains water
Emollient
Greasy
Occlusive
Cold cream, lanolin, hydrocream, eucerin, nivea
```
176
Emulsion; oil in water
```
Insoluble in water, will absorb water
Water washable
Contains water
Nonocclusive
Nongreasy
Hydrophilic ointment, unibase, velvachol, dermabase
```
177
Water soluble base
```
Water soluble, washable
Will absorb water
Anhydrous or hydrous
Nonocclusive
Nongreasy
Lipid-free
Polyethylene glycol ointment
```
178
Creams
Dissolved or dispersed in emulsions (oil-in-water) or water-washable base
Semisolid
Creamy white appearance
Easier to spread and remove than ointments
179
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
180
Paste
Contains larger proportion of solid materials (insoluble solids) than ointments
Stiffer
Less base used: Less greasy than ointments
Zinc oxide paste
181
Problems with topical dosage form classification
```
Not consistent, none are official
Not quantitative, based on opinion
Can overlap (non exclusive)
```
182
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)
183
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.
184
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
185
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
186
Zecuity
Sumatriptan succinate
Iontophoretic transdermal system (TDS)
Caused skin irritation, no longer on market
187
LidoSite (Vyteris)
Pre-filled iontophoresis system of lidocaine/ epi
Treatment of migraine
Wet
Needle free
188
Relationship between fentanyl delivery and electric current
Linear
189
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.
190
Microporation lasers
Creates pore with laser
| P.L.E.A.S.E system
191
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
192
What are microneedles used to deliver?
Water-soluble drugs and macromolecules
193
Alza macroflux microneedle system
Desmopressin- hormone found naturally in the body for increasing urine concentration and decreasing urine production
194
Rapidly dissolving microneedles
Dissolve in 60 minutes
195
3M Microneedle system
polyclonal antibody delivery
196
Microporation: RF-wave
Radiofrequency (RF) to porate skin similar to radiofrequency scalpel
Creates RF- microchannels
GLP-1 agonist and osteoporosis
197
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.
198
Abrasive pads (sandpaper device) to enhance transdermal delivery
TEWL and efficacy of transdermal application were found to increase after treatment
199
ZARS
Controlled heat assisted drug delivery (CHADD) system
| Fentanyl
200
What topical dosage form is not a liquid
Aerosol
Powder
Patch
201
What dosage form is a clear and homogenous liquid?
Solutions
202
What dosage form is a solid dispersed liquid?
Suspension
203
What dosage form is an emulsion?
Lotion
204
What dosage form is a semisolid that contains >50% LOD and is a solution or colloidal dispersion?
Gel
205
What dosage form is a semisolid contains >50% LOD an is an emulsion?
Cream
206
What dosage form is a semisolid that contains a large proportion (20-50%) of dispersed solids?
Paste
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What dosage form is a semisolid that contains >50% of hydrocarbons, waxes. or PEG and <20% LOD?
Ointment
208
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
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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?
210
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
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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
212
Current practice of equivalence
Pharmaceutical equivalence + Bioequivalence= Therapeutic equivalence
213
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
214
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
215
Q3 identical products are ________
bioequivalent
| Ex- topical solutions
216
Direct demonstration for Q3 equivalence is difficult in ______
formulations more complex than solutions
| Ex.- creams, ointments, gels
217
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
218
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
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Active ingredient
Any component of a drug product intended to furnish pharmacological activity or other direct effect in the diagnosis, prevention, cure
220
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)
221
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
222
Oral tablets
SImple compressed tablet (uncoated)
Coated- coated by sugar, film, or enteric
Chewable- rapid disintegration when chewed
223
Direct commpression
Tablets are prepared by direct compression of a drug powder mixed with other excipients
224
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
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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
226
Types of excipients
Fillers (diluents), binders, disintegrants, lubricants, glidants, antiadherents, colors, flavors, sweeteners
227
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
228
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
229
Microcrystalline cellulose
Excipient
| Diluent and binder
230
Lubricants
Reduce friction at the interface of tablet and die wall during compression and ejection
PEG 4000, magnesium
231
Antiadherents
Prevent sticking to the punch and to the die wall
| talc, magnesium stearate
232
Glidants
Improve flow characteristics of granulate
| corn starch, amorphous silica
233
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
234
Disintegrants
Facilitates tablet breakup after administration, hence improve dissolution
cross-linked cellulose
235
Colorants
appearance appeal and identification
236
How to find excipients?
The FDA has a database
| Inactive Ingredient Search for Approved Drug Products
237
GRAS
Generally recognized as safe
| Commonly used as excipients
238
Chemical bulk ingredients
```
USP
NF
FCC
COA
Chemically pure, analytical reagent grade before printed expiration date when stored in original container
```
239
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
240
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
241
Weight variation test
An assay of the drug substance based on weight
242
USP 905 uniformity of dosage unit
The uniformity of dosage units can be demonstrated by either content uniformity or weight variation
243
The orange book
Approved drugs with therapeutic equivalence both OTC and Rx
Cumulative
FDA resource
244
Iontophoresis current
Less than 0.5mA/cm^2
Very small electric current
Unwanted skin reactions occur when current >0.5mA/cm^2
245
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
246
Companion 80 and Hybresis
Iontophoresis
| Has batteries
247
WEDD
Iontophoresis
No batteries
Utilize different metals in the electrodes
Potato example
Cannot control voltage as well but is more patient friendly
248
Lidocaine is _______charged and methylene phosphate is ______ charged
Positively
| Negatively
249
What is the advantage of the dry iontophoresis
You can use a drug off label (dexamethasone)
| Do not have to get approved by FDA
250
2 main advantages for transdermal delivery (iontophoresis)
Reduce onset time
| Increase penetration
251
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.
252
What is more effective, ITS or PCA?
comparable
253
In addition to delivering a drug to the body, what can iontophoresis do?
Extract materials from the body
| Think glucose monitoring system
254
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
255
Does iontophoresis or electroporation increase delivery more?
Iontophoresis
| highest delivery is combination of the 2
256
Which microneedle system injects the drug?
Hollow
257
What are the methods to put wholes in the corneum?
Heat
Microneedles
Lasers
RF
258
Physical enhancers are more useful for
Polar, ionic, macromolecules
259
Heat can significantly increase
Delivery rates and penetration of drug in transdermal delivery
Can lead to OD
260
How much can the stratum corneum swell?
3x
261
Does having the same Cmax and AUC indicate that you have the same concentration in the skin tissue?
No
262
Topical BE cannot be assessed by _______-
Blood circulation
| You can have different tissue and plasma concentrations
263
What are you measuring with in vitro diffusion cell with full thickness skin
Full skin assay
264
What are you measuring with systemic PK and skin biopsy
To the dermis
265
What are you measuring with TEWL
Through the viable epidermis
266
What are you measuring with Tape- stripping
SC
267
What is the purpose of Q1,Q2, and Q3?
To not have clinical trials to establish BE
268
Q3 equivalence is needed for what?
Creams oitments
| Semisolids
269
Q2 is considered BE for what?
Solutions
270
Dibasic calcium phosphate dehydrate
Diluent
271
Lactose, calcium sulfate dehydrate
diluent
272
microcrystalline cellulose, starch
diluent
273
sucrose based diluents, mannitol NaCl
diluent
274
cellular derivatives
binder
275
PEG, starch paste, synthetic gums
binder
276
If you have a small dose of a drug you will see
diluents, fillers
277
If you have a large dose of a drug you will see
Binders
278
PEG 4000, magnesium or Na lauryl sulfate, stearic acid
lubricants
279
talc, magnesium stearate
Antiadherents
280
Corn starch, amorphous silica
Glidants
281
cross-linked cellulose, cross-linked polyvinyl pyrrolidone, modified corn starch
disintegrants
282
iron oxide, titanium oxide
colorants
283
```
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
284
```
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
285
```
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
```
286
Are there any binders in capsules?
No
287
```
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
288
Most inactive ingredients in patches are
adhesives
289
Porous microsphere
Put in gels to capture the lipophilic drugs. Needed because of poor aqueous solubility.
Methyl methacrylate/glycol
290
Why are polymers added to gels?
To increase viscosity
291
Carbomer 940
Polymer in gel
292
hydroxypropyl cellulose
Polymer in increase viscosity
293
If an inactive ingredient is in the GRAS database no additional tests need to be conducted before use T/F
T
294
WV means
You can use weight variation or content verification
