Exam 1 Flashcards
1
Q
Define emulsion, internal phase and external phase
A
An emulsion is defined as a dispersed system containing at least two immiscible liquids
One of the liquids (internal phase) is finely subdivided and uniformly distributed as droplets throughout the other (external phase)
2
Q
Droplet size in emulsions
A
0.1 - 100 Β΅m (nanometers)
3
Q
In an emulsion, one liquid is ______ and one is _______
A
Invariably, one of the two immiscible liquids is aqueous, while the other is oleaginous
4
Q
What are the two types of emulsions? Define them.
A
Oil-in-Water (O/W) Emulsions:
an emulsion in which the oil is dispersed as droplets throughout the aqueous phase
Water-in-Oil (W/O) Emulsions:
an emulsion in which water is the dispersed phase and an oil is the continuous phase (dispersion medium water
5
Q
O/W Emulsion Water Content? What is the internal phase?
A
water > 45% of total weight
oil is internal phase
6
Q
W/O Emulsion Water Content? What is the internal phase?
A
dispersion medium water < 45%of total weight
water is internal phase
7
Q
What is a multiple emulsion? Why were they created?
A
have been developed to produce a sustained release of the active ingredient.
any drug present in the innermost phase must cross two phase boundaries to reach the external or continuous phase (to be available for absorption)
8
Q
Define W/O/W
A
consist of small water droplets which are enclosed in a large oil droplet, which in turn is dispersed in water
9
Q
Define O/W/O Emulsion
A
small oil droplets are enclosed in a large water droplet, which is dispersed in oil
10
Q
What are some advantages of emulsions as dosage forms?
A
Unpalatable drugs can be administered in palatable form
Aqueous phase easily flavored
Oil sensation easily removed
Increased rate of absorption
Easy parenteral adminstrratuion where lipid componenet phase is important
Possible to include two incompatabible ingedirnts; one in each phase of the emulsion
U A O A P I
U ask openly about p** implants
11
Q
Why are emulsions advantageous over suspensions?
A
Bypasses dissolution and makes easier absorption (already in mononuclear phase)
Advantage over suspensions (suspensions in granular form)
12
Q
For oral admin, emulsions are mainlyβ¦.. WHy
A
O/W β> Ensure pleasant taste
13
Q
For intravenous administration, emulsions are mainlyβ¦.. Why
A
O/W β> Other serious embolization may occur
14
Q
Intramuscular administration, emulsions areβ¦. Why?
A
Usually w/o emulsions for depot therapy (sustained release)
15
Q
External administrations are β¦β¦.
A
Emulsified lotions, creams or liniments may be either o/w or w/o depending on their desired use.
16
Q
What are some characteristics of topical O/W emulsions and W/O emulsions?
A
O/W: Not greasy, water-washable
W/O: Greasy, occlusive, form water repellent film
17
Q
What emulsions are lotions, creams, and ointments?
A
Lotions - O/W
Creams - O/W or W/O
Ointments - W/O
18
Q
What are the components of an emulsion?
A
Oil phase
Water Phase
Emulsifying Agent/ emulsifier β> Makes water and oil miscible and provides a homogenous agent
19
Q
What oils are used for the oil phase in oral emulsions? What are they also? Iv? External?
A
liquid paraffin
castor oil
arachis oil (peanut oil)
cod liver oil
LAXATIVES
IV
Cottonseed
Soyabean
Safllower
Topical
Benzyl-benzoate
Turpentine
Various oils (e.g. liquid parrafin) as carriers for active ingredient
Our P* Can Always C* in case someone says that boy takes virgintities
20
Q
What is a fixed-oil? Examples?
A
non-volatile/fatty oil of animal or plant derivation a mixture of esters of fatty acids, usually triglycerides
- Castor oil, Cod liver oil, olive oil
21
Q
What is an essential or volatile oil? Example?
A
non fatty oils from plants
- Mint oil, rose oil, peppermint oil
22
Q
What is mineral oil? Example?
A
- A grade of liquid petrolatum
- Liquid parrafin
23
Q
What may be used for the water phase in an emulsion?
A
Water
Glycerol
Propylene glycol
Polyethylene glycols
Sorbitol
24
Q
Emulsion equation
A
Emulsions = oil + water + emulsifier + energy
25
How do emulsifier stabilize the system in general?
All emulsifying agents concentrate at oil/water interface to provide protection by:
a) Reducing the interfacial tension
b) Imparting a charge on the droplet --> electrostatic repulsion
26
What are the requirements of an emulsyfying agent?
Molecular Structure
Stable Interface
Chemical Stability
Inertness
Non-toxic, non-irritating
Odorless, taseteless, colorless
Non-cost prohibitive
27
How are emulsifying agents classified?
a) Based on chemical structure
i) Synthetic and semi-synthetic
ii) Natural
iii) Finely dispersed solids
iv) Auxillary agents
b) Based on mechanism of action
i) Surface active agents
ii) Hydrophillic colloids
iii) Finely divided solid particles
28
What are the natural emulsifying agent?
Plant Derivatives (mainly water soluble natural polymers) such as tragacanth
Animal derivatives like gelatin, lanolin (w/o), cholesterol and lecithin
29
What are the semi-synthetic emulsyfying agents?
Cellulose derivatives (mainly water soluble polymers) like methylcellulose and carboxymethycellulose
30
What are the synthetic emulsyfying agent?
Polymers like PVP, PEG, or carbomer (hydrocolloid)
Surfactants
31
How are surfactants subdivided?
1. Anionic - Negative hydrophilic head
- Soft soaps alkali metal and ammonium soaps can be formed in-situ, O/W emulsions - - Sodium triethanolamine-stearte
- Hard soaps of divalent and tri-valent metals W/O emulsions - Calcium Oleate
- Detergents sulfated and sulfonated compounds O/W emulsions - Sodium lauryl sulfate
2. Cationic - Positive polar head
- Quaternary ammonium compounds (Benzylklonium, benetholium chloride)
- Used as preservative sin opthalmic formulations
3. Non-ionic
- Most commonly contain an OH and/or ethylene oxide group
- Fatty acid or alchol (12-18 carbon chain)
--> If hydrophobic predominates, surfactant is oil soluble
--> If the hydrophilic portion predominates --> Surfactant is water soluble
- SPANS AND TWEENS
4. Amphoteric
- Carry both a positive and negative charge
-Cationic Part --> primary, secondary or tertuiary amines or quaternary ammonium
- anionic part --> Variable
32
What are the finely divided solids emulsyfying agents?
Form a particulate layer around dispersed droplets --> swell in dispersion medium --> increases inter-particle distance --> minimize inter-particle interaction (process is what makes them have surfactant activity)
Most of them support o/w emulsions. Some like bentonite can form w/o emulsion as well
Viscosity depends on the internal concentration i.e. relative volume of the internal phase
- E.g. bentonite, Veegum
33
What are auxillary emulsifiers?
Weak emulsifiers therefore, always used in combination with other emulsifiers
Stabilize the system by thickening (increasing the viscosity) --> retard inter-particle movement
Examples fatty acids (stearic acid), fatty alcohols (stearyl or cetyl alcohol) or fatty esters (glyceryl mono stearate)
34
How can one choose an emulsifying agent?
Depends on the emulsifying ability desired and the toxicity (determines route of administration) of each emulsifying agent.
35
Why are non-ionic emulsifiers beneficial?
) Non-ionic Emulsifiers
- less toxic, less irritant
36
When can ionic emulsifiers be used?
Ionic Emulsifiers
- should not be given orally (irritant to GIT)
Cationic: toxic at low concentrations --> limited to external use when antiseptic properties are required
Anionic: have high pH (alkaline) --> unsuitable for broken skin
37
What emulsifiers are used for parenteral use?
Parenteral Use
- Only certain types of non-ionic surfactants may be used for parenteral administration
e.g. lecithin, polysorbate 80
38
In regards to the mechanism of action of an emulsifying agent, they are classified according to......
The type of interfacial film formed:
1) Mono-molecular Film
2) Multi-molecular film
3) Solid particle film
39
Define Mono-molecular film
Move from liquid --> liquid interface
--> higher concentration at interface compared to the bulk --> reduces the surface interfacial tension
(surface active agent)
40
Define Multi-molecular film
Causes NO change in interfacial tension and protects coalescence (combination) by:
- Protective sheath around the droplets
- Imparting charge to the droplets --> repel each other
- wetting to increase viscosity --> less likely to merge
(hydrocolloids)
41
Define solid-particle film
Forms particulate layer --> swells --> increase viscosity --> retard droplet movement
(finely divided solids)
42
What is the most common type of emulsifier? What is a structural feature common in all surfactants? The concepts related to the actions of these surfactants will help us decide:
Surfactants
Hydrophilic head and Hydrophobic tail
a) Amount
b) Type
43
Describe amphipathic properties and adsorption at interfaces
- Hydrophobic tail has affinity for oil
- Hydrophilic head has affinity for water
Amphipathic refers to a chemical entity which possesses two distinctly different characteristics, such as a molecule which has both hydrophobic and hydrophilic characteristics (also termed amphiphilic).
44
What occurs at the interface of two immiscible substances? What reduxes it?
When one liquid is in contact with a second liquid in which it is immiscible, the force causing each liquid to resist mixing is called interfacial tension
Surfactants lower the interfacial tension.
45
What do surfactants do in an aqueous medium?
Surface Adsorption
V
Monomers
V
Micelle
46
Describe how surfacatants form micelles?
A low concentration of surfcactant - just adsorption
Surface adsorption increases as concentration of surfactant increases. Surfactant starts to form monomers
At CMC, surfactant concnetration is enough where micelles start to form
47
How are micelles formed?
Micelles are formed by self-assembly of amphiphilic molecules (surfactants).
48
What is the CMC?
the concentration of surfactants above which micelles form and all additional surfactants added to the system will form micelles
49
Define aggregation number
the average number of surfactant monomers in a spherical micelle e.g. 8
50
In an emulsion, do we want a high CMC or a low CMC?
If CMC is low, surfactants form micelles before coating the droplets
Want a high CMC
51
Describe the difference between micelle characteristics with non-ionic and ionic surfactants?
Non-ionic surfactants form micelles at lower concentrations than ionic surfactants
52
Micelles and Monomer Surfactant Relationship
Micelles are in dynamic equilibrium with monomeric surfactant molecules in the emulsion
53
What CMC value of a surfactant do you want for an emulsion?
If the CMC is low --> surfactant will form micelles before oil (or water) droplets can be coated
a surfactant with a low CMC emulsification is not as efficient as one whose CMC is higher
54
What is a mixed micelle?
If a blend of surfactants is used in the preparation of an emulsion --> formation of mixed micelles
55
Describe the lipophile balance?
more hydrophilic emulsifiers,
form o/w emulsions
more lipophilic emulsifiers,
form w/o emulsions
56
What is the numeric system of classifying lipophile balance?
Numeric Measurement = HLB system
57
What is the HLB system?
Assigns each surfactant an HLB number --> its relative polarity
The HLB scale is a numerical scale ranging from 1 to approximately 50
Most surfactants fall between 1-20
58
Describe the solubility of SPANs and TWEENS
If the hydrophobic portion predominates --> surfactant is oil soluble = SPANS
If the hydrophilic portion predominates --> surfactant is water-soluble = Tweens
59
What determines a lipophilic and hydrophilic surfactant?
Low HLB numbers (0-10) -->low polarity -->
LIPOPHILLIC SURFACTANT
High HLB numbers (10-20) --> high polarity -->
HYDROPHILIC SURFACTANT
60
Water Soluble Surfactants and HLB agents. What type of emulsion?
8-16
Emulsifying agents for o/w emulsions
61
Oil Soluble Surfactants and HLB agents. What type of emulsion?
3-8
Emulsyfying agents for W/O emulsions
62
Surfacatants for a stable emulsion?
Combination of surfactant in specific ratios --> more stable emulsion
63
What are spans?
Spans are sorbitan fatty acid esters having low HLB values ranging from 1.8 to 8.6.
Spans are lipophilic
64
What are Tweens?
Tweens (think of W, water) are polyoxyethylene derivatives of spans.
So, they are more hydrophilic having higher HLB values ranging from 10.5 to 16.7.
65
What are the required HLB values for an emulsion?
Oils in the emulsions require
a specific HLB value to be formulated as o/w or w/o emulsion
For the same oil:
If w/o emulsion desired=low HLB value to impart lipophilicity (3-8)
If o/w emulsion desired=high HLB values to impart hydrophilicity (8-16)
66
What is used to obtain the required HLB of the oil?
Mixture of surfactants with high and low HLB values are used to obtain the required HLB of the oil
67
Can a 50-50 blend be used? When and for what?
In some cases 50-50 blend is used as well but only suitable for o/w emulsion (gives final HLB of 10 or greater)
NOT suitable for w/o emulsions which require lower HLB value
68
How can one calculate the amount of tween and span to be used in an emulsion?
HLB mixture = x * HLBA + (1 - x) * HLBB
HLBA --> HLB for hydrophilic surfactant
HLBB --> HLB for lipohlilc surfactant
69
In liquid emulsions, what is the emulsifier combination recommendation?
5% w/v emulsifier combination is recommended for liquid emulsions
w/v = xg/100 ml
70
In regards to making an emulsion, how should one mix the phases?
- Water and Tween together
- Oil and Span together
Always water into oil slowly regardless of o/w or w/o
71
What are anti-oxidants? Examples?
Used to prevent auto-oxidation of oil and lipid components of the emulsion (rancidity)
BHA and BHT are true antioxidants which are synergistic with certain chelating agents (citric acid, EDTA, tartaric acid )
- Never use chelating agents alone. (Binds to free ions in emulsion, chelate it)
- Examples: BHA, BHT, a-tocopherol, alkyl gallates (Propyl Gallate B.P.), ascorbic acid, ascorbyl palmitate
Afford 2 Be
72
What are preservatives? Examples?
Used to prevent growth of micro-organisms
Often lipid and water soluble preservatives are combined:
methylparabens (water phase) and propylparabens (oil phase)
benzoic acid, parabens, chlorocresol
quaternary ammonium compounds
organic mercurial compounds (phenylmercuric nitrate, thimerosal)
73
Why is it important to use the correct preservative?
Emulsion ingredients may inactivate preservatives
micellar binding of preservatives with surfactants
E.g. parabens + polyoxyethylene chains of surfactants (Tweens)
74
What are humectants? Examples?
Humectants are compounds which are capable of absorbing water from the air (reduce evaporation of water phase, if water evaporates, concentration changes)
These agents are used to reduce evaporation of the water phase of an emulsion (to prevent drying of the preparation)
propylene glycol
glycerol
sorbitol
75
What are the type of formulation of emulsions?
a) Dry gum method (continental method)
b) Wet gum method (english method)
c) In situ soap formation
d) Surfactant-based emulsions
76
Describe the differences between the dry gum and wet gum method?
The emulsifying agent is mixed with the oil in dry gum method while it is mixed with water in wet gum method.
The addition of water will be all at once in dry gum method, while the oil is added drop by drop in wet method.
77
What is preferred for emulsions: Glass Mortar vs. Porcelain Mortar
Glass mortar is not preffereed when high sheer energy is needed with natural emulsifying agents like acacaia.
However when surfacatant based emulsions are designed it may be preferred as it offers high surface activity
78
What is the in-situ soap formation method? What type of emulsion does it form?
In situ soap formation (nascent soap method)
emulsifying agent is formed fresh inside the solution.
An oil containing sufficient free fatty acid, such as linseed or olive oil, is placed in a suitable container
An equal volume of alkali, such as calcium hydroxide solution is added
When the mixture is agitated, the fatty acid of the the oil reacts with the alkali to form a calcium soap which, in turn, promotes a W/O emulsion
79
What equipment can be used for emulsification? When are they used?
Mechanical stirrers (rotating blades)
used for high viscosity preparations
large quantities may be mixed
Β Homogenizers (common)
small inlet orifice and pressure is used to incorporate oil
limitation --> not suitable for viscosity > 2000 cP (low viscosity)
Ultrasonifiers
use ultrasonic waves to break down emulsified droplets
produces a uniform emulsion
gentle --> powerful
Β Colloid Mills (rotor/stator)
frequently used
Industry --> Scaling up production
80
What labels should be used for emulsification?
Shake well (may or may not be refridgerated)
+/- For external use only
Oral --> Must have refrigeration
81
What is the most important requirement of an emulsion?
The most important requirement of a well-formulated emulsion is that it possess adequate physical stability.
A stable emulsion is one in which the dispersed droplets retain their original characteristics and remain uniformly distributed throughout the continuous phase.
82
What are the thre eprimary phenomenons associated with physical instability of emulsions?
Creaming or Sedimentation
Flocculation
Coalescence (breaking, cracking) --> DONE (need to start over)
83
Describe how creaming or sedimentation occurs. How is movement determined? Why is it undesireable?
Β·Β Β Β Β Β Β Β Dispersed droplets in an emulsion may move either upward (creaming) or downward (sedimentation) within the continuous phase
Β·Β Β Β Β Β Β Β The direction of movement is determined by the density of the droplets relative to the density of the continuous phase
Β·Β Β Β Β Β Β Β Creaming/sedimentation is undesirable because the emulsified product must remain homogeneous to deliver a correct/uniform dose
Β·Β Β Β Β Β Β Β These processes also increase the possibility of coalescence of adjacent droplets.
84
What is stokes law?
Stoke's Law calculates rate of destabilization of an emulsion by equating gravitational force with the opposing hydrodynamic force.
Stoke's Law can be used to predict emulsion stability
85
How can the rate of creaming/sedimentation will be reduced by:
Decrease droplet size (homogenization)
Decrease in the density difference between the two phases (not used in practice)
Β
Increase the viscosity of the continuous phase (e.g. with hydrocolloids)
control of the disperse phase concentration (β 20 - 60%)
86
What is teh main difference between creaming/sedimentation and coalescence?
Emulsions which have creamed or sedimented will still have good re-dispersibility. Coalescence is irreversible.
87
What is stokes law?
V = d2 (po - pw) g / 18n
v = velocity/rate of sedimentation
d= diameter of spherical particles
po = density of oil (g/cm3)
pw = density of water
g= acceleration due to gravity (981 cm/sec2)
n= viscosity of the dispersed medium
A negative value indicates upward movement (creaming)
88
Describe the DLVO system.
DRAW IT OUT
DLVO theory suggests that the stability of a colloidal system is determined by the sum of these van der Waals attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach each other due to the Brownian motion they are undergoing
The secondary minimum --> easy dispersion. Occurs readily but re-dispersion is easily achieved by shaking
The primary maximum --> repulsion is greater than attraction --> particles are going to avoid each other --> stay more dispersed IDEAL STATE OF DISPERSION
The primary minimum indicates that the aggregated state is of the lowest-energy condition and this is where we would expect the particles to reside .More serious and re-dispersion is difficult (everything is together)
89
What is coalescence?
Coalescence is the complete fusion of droplets within an emulsion, which leads to a decreased number of droplets and ultimately separation of the two phases
90
How does resistance to coalescence occur in W/O and O/W emulsions?
Resistance to coalescence in o/w emulsions is provided by the strength of mono- or multimolecular films.
Coalescence in w/o emulsions is prevented by the presence of long hydrocarbon chains of surfactant molecules which project into the oil phase.
91
What beyond use dates should be used for emulsions?
Should be conservative even for chemically stable ingredients --> physically unstable system
Usually 14 day dating for all water containing preparations when ingredients are in solid form and chemical stability of the system is unknown
For simple preparation and external use preparations like zinc oxide and calamine lotion are stable --> 1 month dating is satisfactory
Oral emulsions --> store in refrigerator to enhance taste and maintain microbiological stability
92
What is the difference between dispersed medium and dispersed phase?
Dispersion medium is the continuous phase in which the dispersed phase is distributed throughout.
Dispersed phase is the phase that is composed of particles that are distributed through another phase.
93
What are some advantages of dermatological preparations?
Allows combimatorial tx strategies
Allows localizes drug action limiting systemic side effects of medications
Lower dosages
94
What are some disadvantages of dermatological preparations?
Slow onset leading to longer tx times
Significant dependence on PC properties as the topical formulation has to overcome the protective barrier of the skin at therapeutically effective concentrations
May enocunter disease specific limitations
Skin changes over time as we age
95
What is the largest organ in the body?
SKIN
96
What is the average thickness of the epidermis?
Average thickness: 200ΞΌm generally while 800ΞΌm on palms and soles, 60ΞΌm on eyelid
97
What is the pH of the epidermis?
pH=5.5 (acidic)
98
What is the epidermis composed of?
Composed mainly of keratinocytes which synthesize keratin (insoluble protein), melanocytes and dendritic (Langerhans) cells which are immune cells that determine appropriate adaptive immune response
99
What are the five layers of the epidermis?
Stratum corneum (horny layer)
Stratum lucidum (clear layer)
Stratum granulosum (granular layer)
Stratum spinosum (prickle cell layer)
Stratum germinativum or Stratum basale (basal layer)
Can H**** Lads Come Get Some Pretty Ginger B****
100
What is the main barrier to percutaneous absorptin?
The stratum corneum of the epidermis
101
The stratum corneum. What is its role?
10-15 layers of flattened keratinized anucleated dead cells
Undergoes desquamation (natural process to remove dead cells)
Role:
major permeability barrier of the skin that controls percutaneous absorption
102
What is desquamation? Why is it important?
It is skin's way of recovering or healing from some type of damage.
It is a process where cells from the top outer layer of the skin known as the stratum corneum is removed.
Skin can only be optimally healthy when it has a normal rate of natural desquamation.
This is because desquamation enables skin to continuously create a uniform brick and mortar structure of dead skin cells packed together by lipid glue.
It also creates a barrier which enables skin to retain hydration and resist assault.
103
What is the stratum lucidum (clear layer)? Role?
Thin layer of translucent, extremely flattened cells, only visible in the thickest skin
Anucleated cells
Cytoplasm filled with filaments
Role:
responsible for the capability of the skin to stretch.
contains a protein that is responsible for the degeneration of skin cells
Lowers the effects of friction in skin, especially in regions like the soles of feet and palms of hands.
104
What is the straum granulosm? Role?
1-5 layers of flattened, many-sided cells
Keratinocytes contain keratohyalin granules which discharge a cement-like substance that bind cells together (barrier against foreign material)
- Last layer of living cells
Role:
Site of biochemical activity (bioreactor) β metabolism occurring here in cells
105
What is stratum spinosum (prickle cell layer)? Role?
Cuboidal, many sided or flattened keratinocytes
Keratinocytes contain bundles of filaments (βpricklyβ looking) Subject to constant pressure and friction
Role:
helps the skin resist abrasion
106
What is the straum germinativum layer? Role?
Cells held together by desmosomes (tiny Velcro-like patches)
Single layer of cuboidal or columnar cells
Nucleated basal cells (undergo mitosis)
Turnover time 28 days (4 days in psoriasis)
Role:
provides the germinal cells necessary for the regeneration of the layers of the epidermis
107
What is the dermis composed of?
Matrix of connective tissue (75% collagen, 4% elastin)
Cells (fibroblasts, mast cells, histiocytes)
Vascular supply
Neural supply
Skin appendages (sweat glands, sebaceous glands, hair follicles)
108
What is the thickness of the dermis?
Thickness 3-5mm
Presence of nerves and blood vessels (provide O2 and nourishment)
109
What is the role of the dermis?
Support
Thermoregulation
Aid in sensation
Provide O2 and Nourishment
110
What is the ph of the dermis?
Average pH: 7.2 (neutral β closer to physiological pH)
111
The subcutaneous tissue consists of.......
Hypoderm
Subcutis
112
What is the composition of the subcutaneous tissue?
Fibrofatty layers
Also house immune cells like macrophages
113
What is the role of the subcutaneous tissue?
storing energy
connecting the dermis layer of your skin to your muscles and bones
insulating your body
Mechanical cushion
114
What are some functions of the skin?
a) Mechanical
Elasticity β stretch 1.5x
Stratum corneum requires 10-20% water to be able to bend easily, otherwise it cracks and splits
b) Protective
Microbiological barrier β acid mantle pH 4.2-5.6 is bacteriostatic and fungistatic
Radiation barrier - UVB burns skin and is more damaging than UVA
Heat regulation β eccrine glands thermoregulate by water evaporation of sweat, vasoconstriction (shivering, goosebumps), vasodilation (reddening)
C) Chemical barrier
Stratum corneum is 10,000x less permeable than other membranes
Compounds penetrate easier through diseased skin
Amount of transport through the shunts (areas around hair follicles and glands) is negligible
115
What is the major rate-limiting barrier to drug delievery?
STRATUM CORNEUM
116
How can topical delivery be controlled?
o The stratum corneum is the rate-limiting barrier to transdermal drug delivery
o The different morphologies (flattened, columnar, cuboidal) are a mechanical barrier for transport of drugs
o Bioreactor activity β enzymatic activation/inactivation of drug
o Immune cells can affect the survival of APIs
117
What is the role of dermis in topical drug delievry?
When drug reaches the dermal layer, it becomes available
for systemic absorption via the dermal microcirculation
βsink effectβ (drugs do not accumulate in the skin βthe
concentration gradient exist to partition the drug.
118
What is the role of the SQ in regards to drug delivery?
Fatty cells aids in transport of lipophilic drugs.
Macrophages may impact stability of biomolecular
therapeutic entities.
Injectable drug delivery to subcutaneous tissue is more
common than topical therapy (USED FOR LIVE
VACCINE ADMINISTRATION and ANTI-DIABETIC
DRUGS PROTEINS (INSULIN) and PEPTIDES (GLP-1
ANALOGUES)
Factors like aging affect the fatty composition of this layer
affecting transdermal drug absorption
119
What are some important aspects to target dermatological drug delievery?
Pathophysiology of the disease condition
Active ingredient characteristics
Intended therapy (localized vs. systemic)
Vehicle/drug delivery system
120
What is the physiochemical criteria of dermatological formulations?
Stability of the active ingredient
Stability of adjuvants
Rheological properties (consistency, extrudability)
Prevention of loss of water or volatile compounds
Phase changes β homogeneity, phase separation, bleeding)
Particle size, particle distribution of the dispersed phase
Apparent pH
5 P's
121
What are the cosmetic (esthetic) criteria of dermatological preparations?
Pharmaceutical elegance βpoor product may lead to non-compliance
Easy transfer from container
Spreads readily and smoothly
Leaves no residue or stain
Adheres to treated area without being tacky or difficult to remove
122
What factors are used for the selection of a vehicle for optimal bioavilability?
Skin disease or condition
Rate of the release of the drug from the vehicle (drug favors skin over vehicle)
Promotion of percutaneous absorption
Requirement for occlusion
Short- and long-term stability of the drug in the ointment base --> anti-oxidants
Influence of the drug on the consistency of the base
Can Drops????
123
Define Ointment
Contains β€20% water and volatiles and β₯50% of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external application to the skin
124
Define cream
An emulsion semisolid dosage form that contains >20% water and volatiles and <50% of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external application to the skin
125
Define paste
A semisolid dosage form that contains a large proportion (i.e. 20-50%) of solids finely dispersed in a fatty vehicle for external application to the skin
126
Define gel
A semisolid dosage form that contains a gelling agent to provide stiffness to a solution or colloidal dispersion for external application to the skin. A gel may contain suspended particles
127
Ointments appearance:
o Greasy and mostly anhydrous
128
What are the different ways to compound an ointment?
Fusion β all components melted together then cooled with constant stirring until congealed. Start from the highest melting point then decreasing is most often used. Uses a stainless steel mortar
Incorporation β mix one semisolid into another via geometric dilution. Can either be with a mortar and pestle or with a slab and spatula.
Incorporation of solid APIs using a levigating agent such as mineral oil or isopropyl myristate (also a penetration enhancer)
Incorporation of liquid APIs or excipients
Drug is liquid (e.g., benzoyl benzoate)
Drug is dissolved in an oil
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BUD
USP
* 30 days for water containing topical
* 14 days for non-preserved aqueous
* 35 days for preserved aqueous
* 90 days for non aqueous
Medisca
* Ointments 28 days
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Describe the bases pathway:
LOOK at Graph
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Hydrocarbon/oleaginous bases effects:
Non water washable, greasy, stain clothing, hard to remove, lower adherence
Occlusion β forms an impermeable layer on the skin that prevents evaporation of water
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What are the effects of oleaginous bases on the skin?
increases hydration, enhances percutaneous absorption, emollient
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Why are oleaginous bases used for topical formulations?
Stable, non-irritating, non-sensitizing, high drug compatibility
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Main Ingredients of Oleaginous Bases
* Liquids β fats and fixed oils (mono-,di-, and triglycerides) may become rancid, mineral oil
* Semisolids β petroleum and white petroleum
* Solids β waxes (stiffening agents, emollients), paraffin
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Additives in Oleaginous Bases. Example:
* Penetration enhancers β fluidization of stratum corneum lipids. Examples: isopropyl myristate, oleic acid, oleyl alcohol.
* Levigating agent β aids in particles size reduction, maximum 5% of final formulation. Example: mineral oil.
* Does NOT need preservatives as no water
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Absorption bases appearance/charcteristics?
Non water washable, greasy, anhydrous base containing a hydrophilic component provide water absorbing properties
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How do absorption bases work?
Upon water addition they form w/o emulsions. They are emollients
Contain oleaginous material and a water in oil emulsifier so they can absorb water to expand w/o emulsions
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What conditions are oleaginous bases used for?
Oozing conditions
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What are the different types of absorption bases?b
Type 1 (anhydrous bases) β glyceryl monostearate and glyceryl monooleate, cholesterol. Used for specialty compounding
Type 2 (lanolin) β can take up to two times its weight in water, w/o emulsifier
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What can be added to absorption bases?
* Antioxidants
* Penetration enhancers
* Levigating agent β could be hydrophilic (glycerol, propylene glycol)
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Emulsifying bases are also known as
Water washable bases
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What are emulsifying bases? What do they look like?
Water washable (miscible with water), anhydrous base containing an o/w emulsifying agent, self-emulsifying, emollient
Cream-like appearance
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What are the main componenets and additional componenets of an emulsifying base?
Main components:
* Fats and fixed oils
* Mineral oil
* Petroleum and white petrolatum
* Waxes
Additional components:
* o/w emulsifiers (surfactants)
* antioxidants
* penetration enhancers
* levigating agents (can be hydrophilic)
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Characteristic of water-soluble bases:
Water Washable; miscible with water
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Levigating agents can take up to:
No more than 5% of total weight
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How much water in water soluble bases?
ο§ Cannot take up more than 8% water (loose consistency)
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Water Washable Bases Concern Examples
ο§ Incompatible with a lot of other excipients.
They reduce the antimicrobial activity of quaternary ammonium compounds and parabens.
They inactivate bacitracin and penicillin.
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Water-washable bases Additives. Are preservatives and humectants necessary?
* Antioxidants β must be water soluble
* Penetration enhancers
* Do not need antimicrobial preservatives or humectants as they are anhydrous formulations
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Water-washable bases Compounding Methods
* Fusion mostly
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Main Parts of an Emulsion
Oil phase: all liquid, semisolid and solid excipients used for oleaginous bases
Fats and fixed oils
Mineral oil
Petrolatum (USP) and white petrolatum (USP)
Waxes
PLUS
Water phase
Additional components
emulsifying agents, mostly surfactants
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Fusion: Highest First or Lowest
Commonly Start with highest then work downwards
The reason for starting with the lowest is that as you add further components they will dissolve in the molten ingredients and do not necessarily need to reach their melting point.
Also starting in this order may limit the high heat exposure for APIs (if heat labile nature is a concern) and allows more rigorous temperature control.
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Compare the two types of emulsions
W/O:
Greasier than O/W emulsions
Non water washable
Emollient, cleansing action (cosmetic application is more common)
Capable of absorbing oil-soluble compounds from the skin
O/W:
Water washable
Soft
Non-occlusive
Moisturizing (increases water content restores hydration of the skin)
More commonly seen medicated creams are O/W emulsions
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What do humectants do? High and low cocnnetration? Examples?
Increase the hydration of the skin at low concentrations
Withdraw moisture at high concentrations
Prevent product from drying out
Sorbitol, Glycerol, propelyne glycol, PEG
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Rate the anti-oxidants in water soluble and oil soluble
Oil-soluble antioxidants
butylated hydroxy toluene (BHT) and butylated hydroxy anisole (BHA)
Ξ-tocopherol
Water-soluble antioxidants
Ascorbic acid
Sodium bisulfit
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Process of Compounding Creams
Method # 1 Fusion
1. Hydrophobic components melted together
Melting starting with LOWEST melting point
2. Hydrophilic components dissolved in the water phase and heated 5Β°C higher than oil phase
3. Water phase added to oil phase gradually with constant stirring
4. Cooled with constant stirring until congealed
Method # 2 Incorporation
Mixing of one semisolid formulation into another
In a mortar with pestle
On a slab with spatula
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Main componenets of paste base?
Hydrocarbon bases: all liquid, semisolid and solid excipients used for oleaginous bases
Fats and fixed oils
Mineral oil
Petrolatum (USP) and white petrolatum (USP)
Waxes
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Paste Characteristics
Containing 20% to 50% powder dispersed in fatty base
Very stiff consistency β localize materials to defined areas of the skin
Form a thick impermeable layer on the skin β protective action
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Compounding of pastes. Do we use a levigating agent?
Fusion β can be used to prepare the base
Incorporation β method of choice for final formulation
Incorporation method on glass slab is a method of choice due to the thickness of the formulation
It is impractical to use a levigating agent.
Safety considerations are important for irritable APIs like salicylic acids
Packaging can be done in
ointment jar or small
ointment tube depending
on the quantity
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What are the benefits of water soluble bases?
Anhydrous --> useful for drugs that hydrolyze
Good patient compliance β non-staining, non-occlusive
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What is a gel?
Liquid-rich, two-component semi-solid colloidal systems
Natural or synthetic polymers form a three-dimensional matrix throughout a hydrophilic liquid
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What bases do gels use?
Water washable bases
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Gel properties
Dissolve in water
Good for hairy areas
Good for oily skin textures
Water-soluble drugs are easily incorporated either dissolved in the aqueous phase or dispersed in gel
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Main componenets of gels
Natural gums: tragacanth, agar, pectin, alginates
--> * Hazy in appearance, high stickiness, microbial contamination
Semi-synthetic or synthetic polymers: methylcellulose, hydroxymethylcellulose,
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Additives of gels
Anti-oxidants - Water soluble
Penetration Enhancers
Antimicrobial Preservatives
Humectants
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Compound Method of Gels
HYDRATION
Common thread: full hydration is slow, most of the time takes 24 hours. Exact method depends on the type
o Must adjust pH to make sure it gels, keep refrigerated overnight for full hydration
