1
Q
What are the different types of capsules?
A
- Gelatin
- Methyl cellulose (HPMC) [best to use in DPI]
- Calcium alginate
- DRcaps™ Gastro Resistant Capsules
2
Q
What are the steps for gelatin manufacturing?
A
- Derived from skin or bone
- Acid or alkali treatment
- Extended treatment periods
- Filter
- Vacuum concentration
- Cool to solidify
- Air dry
- Mill to size
3
Q
How can capsules be closed?
A
- welded with heated metal pin
- bonded with molten gelatin
- snap fit
- coni-snap
4
Q
Properties of soft gelatin capsules
A
- Shells of gelatin, glycerin or sorbitol added to induce plasticity
- Oblong, elliptical or spherical shape
- Used to encapsulate liquids, suspensions, pastes or dry powders
- Must be prepared filled and sealed in one continuous operation
5
Q
What are the ways in which you can manufacture soft gelatin capsules?
A
- plate process
- die process
6
Q
What does the die process consists of?
A
- a process which to manufacture soft gelatin capsules
- rotary process
- reciprocating process
7
Q
What is the plate process?
A
- a process which to manufacture soft gelatin capsules
- molds
8
Q
What types of formula is suitable for soft gelatin capsules?
A
- Water immiscible, volatile and nonvolatile liquids
- Oily, non-volatile liquids
- Not suitable for low molecular weight compounds that can easily pass through the capsule
9
Q
What are the different types of coating for coated tablets?
A
- Sugar
- Film (make tablet more sturdy)
- Gelatin
- Enteric
10
Q
What are the types of specialized tablets?
A
- chewable
- effervescent
- CR, ER
- sublingual
- buccal
11
Q
What are the essential ingredients for tablets?
A
- diluent
- binder
- lubricant
12
Q
Why would any ingredient be essential to tablets?
A
give the formula specific characteristics needed to be compressed
13
Q
What are the ingredients to give tablets desirable characteristics?
A
- disintegrant
- color
- flavor
- sweetening agent
14
Q
What is the purpose of a glidant?
A
- needed for formulations with poor flow
- not needed if lubricant is enough for flow
- improves flow characteristics of powder mixture
15
Q
Define diluent
A
inert substance added to increase bulk to make a tablet of practical size for compression, or to adjust its size
16
Q
What are examples of diluent?
A
- lactose
- calcium phosphate
- microcrystalline cellulose (Avicel®)
17
Q
There needs to be a compatibility test between diluent and active ingredient. Give an example of an incompatibility.
A
Calcium salts interfering with absorption of tetracycline in the GI tract
18
Q
How can a diluent affect bioavailability?
A
water soluble diluents can increase bioavailability of drugs that have low solubility; can enhance dissolution
19
Q
Define binder
A
glues ingredients together and helps with compression; improves powder flow-ability
20
Q
What are examples of binders?
A
- starch (10-20% paste)
- gelatin (10-20% solution)
- acacia
- CMC
- PVP
21
Q
What is the purpose of a lubricant?
A
generally hydrophobic; to prevent adhesion of the powder formulation to the surfaces of the dice and punches of tableting machine; improves rate of flow of granulate; should be added after granulation
22
Q
What are examples of lubricant?
A
- talc (1-5%)
- magnesium stearate
23
Q
Why does talc undergo testing?
A
it may contain metals
24
Q
What happens if you add too much lubricant?
A
- your tablet may become waterproof and it will affect wetting of the tablet
- lead to poor tablet disintegration
- poor dissolution
- decreased solubility
25
Give an example where talc needs to be purified.
if talc is not pure enough, it may have a high Ca concentration and will act as a decomposing agent towards ASA
26
What is an example of a glidant?
talc
27
Define disintegrant
substance or mixture of substances added to a tablet to facilitate its break-up or disintegration after oral ingestion
28
What are examples of distinegrants?
- starch
| - celluloses
29
How can you tell the difference between the roles that starch plays?
- dilute/dissolve starch = binder
- mixed with diluent = used as disintegrant
- starch used as a binder usually has a lesser proportion
30
Why doesn't effervescent tablets need disintegrants?
because the sodium bicarbonate, tartaric or citric acid effervescence will cause tablets to disintegrate
31
Which are the steps that we can add coloring agents and why?
- wet granulation: dissolved in binding solution prior to granulation
- dry granulation: blended in dry with other ingredients
32
What are examples of flavoring agents?
- Cyclamates and saccharine (banned)
| - Aspartame
33
What does it mean when you have talc and magnesium stearate in the same compound?
one will act as the glidant and one will act as the lubricant
34
What are the purpose of tablet coating?
- cover unpleasant taste, odor, color
- physical and chemical protection
- DR or EC
- identification
- ease process of blistering
35
What are the different kinds of coatings?
- sugar coated
- film coated
- gelatin coated
- enteric coated
- compression coated
36
Purposes of sugar coating
- protection from air and humidity
| - improve taste and smell
37
What can be used to waterproof tablets?
Shellac
38
What is used to smooth tablets?
dibasic calcium phosphate, titanium oxide, starch
39
Purposes of film coating
- improve presentation
- increase stability
- improve taste
40
What are examples of plasticizers and how are they used in tablets?
- used for film coating
| - castor oil, diethyl phtalate, propylen glycol
41
What are examples of enteric coating materials?
- cellulose acetate phtalate
- poly(methacrylic acid-co-methyl-methacrylate)
- poly(vinyl acetate phtalate)
42
What are some commercially available for use enteric coating solutions?
- Aquateric®
- Caoteric®
- Eudragits™
43
Explain how enteric coating tablets allow the API to be released in the intestine instead of the stomach.
- At low pH, carboxyl groups remain protonated (not water soluble)
- At high pH, carboxyl group is ionized (becomes water soluble)
44
Describe ingredients in sublingual tablets
lactose or mannitol and saccharine is massed with 60% ethanol
45
What are ingredients in buccal tablets?
- lactose or mannitol
- HPMC
- silica gel
46
With respect to the film theory, what is a stagnant film?
a layer of solution which is saturated with the drug
47
Define sink condition
one-third times that of the maximum solubility of the drug
48
What are factors that influence dissolution from solid dosage forms?
- dosage form
- solubility
- dissolution media
- partition coefficient
- diffusivity
- diffusional path thickness
49
What are three interaction forces that occur in powder samples?
- capillary forces
- mechanical interlocking
- electrostatic charges
50
What are the main reasons to granulate pharmaceutical powders?
- make particle size more uniform
- improve powder flow
- improve compression characteristics of the drug
- densify materials
51
What are examples of plasticizers and how are they used in soft gelatin capsules?
- used to soften gelatin and make it more maleable
| - sorbitol, glycerin
52
What are the ways in which tablets can disintegrate?
- wicking: disintegrant forms pored and water enters the pores which reduces the physical bonding forces between powder particles
- swelling: disintegrant particles swell inside tablet breaking the tablet from the inside
53
What are the advantages of a film coating over sugar coating?
- simpler process
- less ingredients in coating solution
- can provide thinner coats
54
Causes of capping / lamination
- insufficient binder
- undermixing of tablets ingredients
- fast speed of compression
55
Causes of sticking / picking
- insufficient amount of lubricant
| - improper application of coating or insufficient drying time
56
Causes of erosion / chipping
- tablets are friable
- fast pan rotation during coating
- poor choice of plasticizer
57
Causes of bridging
- high viscosity of solid content in coating solution
- improper atomization pressure
- insufficient drying time
- slow pan rotation during coating
58
What are different types of media for dissolution?
- water
- solution with buffer
- simulated gastric fluid (SGF)
- simulated intestinal fluid (SIF)
59
What does SGF consists of?
- 0.2% NaCl in 0.7% HCl
| - pepsin
60
What does SIF consists of?
- Phosphate buffer, pH=6.8
| - pancreatin
61
Apparatus 1
- rotating basket
- less than 4h dissolution test
- standard volume 900-1000mL (also 1, 2, and 4L)
used for
- tablets coated, IR, DR, EC
- capsules
- beads
- suppositories
- floating dosage forms
62
Apparatus 2
- paddle
- makes up about 80% of dissolution tests performed
- less than 4h dissolution test
- standard volume 900-1000mL
used for
- tablets coated, IR, DR, EC
- capsules
- beads
- floating dosage form
63
Apparatus 3
- reciprocating cylinder
- 4-12h dissolution test
- standard volume 200-250mL
used for
- controlled release tablets & beads
64
Apparatus 4
- flow-through cell
- designed for poorly soluble compounds
- flow rate: 10-100mL/min
used for
- low solubility drugs
- microparticles
- implants
- suppositories
- controlled release formulations
65
Advantages and disadvantages to Apparatus 4
- Advantages: easy to change pH, pH profile, sink conditions maintained at all times, open and closed system, can be automated
- Disadvantages: de-aeration necessary, high volumes of media needed
66
Apparatus 5
- paddle over disk
- standard volume = 900m L
- used for transdermal patches
67
What should the time period be for an IR tablet to be dissolved?
15 - 60 minutes
68
What are the sizes of particles that get stuck in to nasopharyngeal region?
10-30 microm
69
What are the sizes of particles that get stuck in to bronchiolar region?
5-10 microm
70
What are the sizes of particles that get stuck in to alveolar region?
1-5 microm
71
What are local advantages of nasal drug delivery?
- Ease of administration
- Rapid absorption and onset of action
- Reduction in systemic side effects
72
What are systemic advantages of nasal drug delivery?
- Rich vasculature underlining the nasal mucosa
- does not undergo first pass metabolism
- Rate and extent of absorption similar to IV (for some drugs)
73
Disadvantages of nasal delivery
- Small site for absorption
- Mucociliary clearance
- Potentially short residence time
- Efficiency of delivery is important
74
What does formulation enhancers do to the drug?
- increase absorption
| - increase time spent in cavity via mucoadhesives
75
What happens with chronic use of formulation enhancers for nasal routes?
nasal irritation
76
What are the types of dosage forms for nasal delivery?
- solution: drops, spray pump
- suspension sprays
- gels
- emulsions and ointments
- DPI
77
Factors that affect drug absorption
- size of drug molecule
- partition coefficient (lipid solubility)
- drug concentration
- ionization state of drug
- pH of absorption site
- vehicle for drug delivery
- mucosal contact time
78
What are the types of solubilizers or co-solvents for nasal dosage form?
– Alcohol, 200 proof (2%)
| – Propylene glycol (20%)
79
What are surfactants used for in nasal dosage form?
to reduce surface tension for drug to penetrate membrane
80
What are tonicity agents used for in nasal dosage form?
so that tonicity in the nasal membrane is isotonic so it doesn't get damaged
81
What is a popular bioadhesive?
chitosan
82
What are types of local action which nasal formulations can target?
- rhinitis
- nasal pruritus
- sinusitis
- runny nose (rhinorrhea)
- prevent polyps
83
What are types of systemic advantages which nasal formulations can achieve?
- convenient
- more efficient dose/effect (propanolol)
- avoid first pass metabolism
84
What are the effects of nasal route to the brain?
- bypasses BBB
- delivered via neural pathways
- minimize systemic exposure
85
Describe the size requirements for delivery to brain from nasal route.
make sure the droplet sizes are on the lower side (10 micron) so that it's more sensitive to the upper concha to go to the brain
86
Define aerosol
dispersion of particles or droplets suspended in a gas or vapor
87
What are advantages of local delivery with respect to pulmonary route?
- can treat asthma, COPD
- rapid onset
- no interactions with food
- more acceptable then injections
88
What are advantages of systemic delivery with respect to pulmonary route?
- avoids first pass metabolism
| - large surface area: (120 – 160 m2, ~ tennis court)
89
What are limitations of pulmonary route?
- lungs designed to prevent inhalation of exogenous compounds / particulates
- oropharyngeal irritation, taste
90
Define aerodynamic diameter
“How well the droplet or particle can fly in a stream of air”
91
What are the types of aerosol deposition?
- for >5 microm: electrostatic attraction, interception, impaction
- for <5 microm: gravitational settling (sedimentation), brownian diffusion
92
What is the purpose of holding your breath when inhaling an aerosol?
- no air exchange to decrease air velocity going down
- droplets fall down deeper
- enhancing sedimentation of aerosol
93
What is the preferred value of Geometric Standard Deviation (GSD) for particle size for inhalation? And what does this mean?
2; means that 95.5% of particles are at the site of action
94
How do you measure diameter of particles?
- individual free particle
- aggregation will act like a larger particle
- droplets which have free particles, particles will assume their free diameter inside the droplet
95
What is the important of density influencing deposition?
if a particle is larger in diameter but less in density, it can still act as if it is a small particle
96
What can hygroscopic particles do?
can absorb humidity in resp. tract and assume a larger diameter than intended
97
What are two conditions (that we talked about in class) that can be treated by nebulization?
- cystic fibrosis
| - emphysema
98
What are types of nebulizers?
- air jet (makes up majority)
| - ultrasonic
99
What are advantages of nebulizers?
- Aqueous solutions: no environmental concerns
| - Does not depend on patient inspiratory force
100
What are disadvantages of nebulizers?
- Bulky / Not portable
- Equipment is not cheap
- Device designed independent of drugs; can lead to waste
- Contamination of device
101
With respect to nebulizers, what does droplet size depend on?
- volume of solution
- surface tension
- density and viscosity
- nebulizer equipment
102
Describe the events that take place in an ultrasonic nebulizer
- Energy generated to piezoelectric transducer
- Shakes to coupling fluid which goes to drug solution
- Droplets are formed
103
Advantages of ultrasonic nebulizer
can created smaller particles
104
Disadvantages of ultrasonic nebulizer
- complex apparatus
- cannot be used by particles degraded by heat
- not easily cleaned
105
Characteristics of solutions used for inhalation
- pH close to neutral
- iso-osmotic
- isotonic (if not, can cause vasoconstr.)
106
What is an example of advancements in nebulizers?
- AKITA JET used in Germany to treat CF
| - tracks doses taken and doses missed
107
What are classes of drugs that can be used to treat asthma?
– Beta2-adrenergic agonists
– Glucocorticoids
– Mast cell stabilizer
108
Define MDI
Devices that contain a pressurized formulation that is aerosolized through an atomization nozzle; doses are metered
109
Advantages of MDI
- portable
- easy to use and convenient
- drug is protected from light, O2, and water
- tamper proof
110
Disdvantages of MDI
- enpensive
- prone to incorrect use
- pressurized contents
111
Specific to MDI, particle size released from MDI depends on what?
- formulation
- valve design
- actuator
- propellant
112
What are the uses for propellants in MDI's?
– Provide pressure to expel product
– Also act as dispersion medium
– Occasionally exhibit solvent properties
113
What are the uses for solvents in MDI's?
– Bring active ingredient into solution
– Co-solvent for immiscible liquids
– influence particle size
– reduce vapor pressure
114
What is the Montreal Protocol?
- CFC [Chlorofluorocarbons] were killing the ozone layer; mandate to stop using it
- HFA [Hydrofluoroalkanes] used in its place and transition all to HFA by 2005
115
What effect does vapor pressure have on formulation performance in MDI's?
- particle size
- droplet evaporation
- velocity
116
Advantages of DPI
- does not require coordination with actuation (but do breathe in with full force)
- don't have to worry about solubility
- less likely that microbe will grow in powder
- can deliver higher doses
- tamper proof
117
Disadvantages of DPI
- breathe in with full force (not recommended for children or elderly)
- strength of pt's airflow determines dose administered
- active DPI may be expensive
118
Sedimentation that occurs between bronchiolar and alveolar region has to be what size?
3-5 microm
119
Diffusion occurs where and what size does it have to be?
alveolar region at <1 microm
120
What are the major components of an MDI?
- canister
- valve
- actuator
121
What are five symptoms / diseases that nasal formulations can be used for?
- seasonal allergies
- pain
- migraine
- smoking cessation aids
- influenza vaccine
122
What are humectants used for in nasal products?
to avoid dryness of nasal cavity while using medication
123
What are solubilizers used for in nasal products?
to increase the concentrations of drugs that have poor aqueous solubility
124
How do you apply semi-solid preparations?
topically
125
What are examples of non-medicated semi-solid preparations?
- emollient (moisturizer)
| - skin protectant
126
What are the classifications of bases for semi-solids?
- oleaginous
- absorption
- water removable
- greaseless
127
other names for oleaginous bases
- hydrocarbon bases
| - hydrophobic bases
128
oleaginous base properties
- highest occlusion properties
- most oily
- difficult to wash off skin
- difficult to incorporate aqueous agents
- immiscible with water
- used to protect skin and emollient effects
129
examples of oleaginous bases
- regular and white petrolatum
| - yellow and white ointment
130
absorption base properties
- able to absorb aqueous solutions to give w/o emulsion
- used for emollient effects
- difficult to wash off skin
131
examples of absorption bases
- hydrophilic petrolatum
| - lanolin (wool fat)
132
water removable base properties
- also known as water washable
| - external phase has to be water; o/w phase
133
example of water removable bases
hydrophilic ointment
134
greaseless base properties
- water soluble
- good for incorporating solid compounds
- soften with addition of water
135
example of greaseless bases
PEG ointment
136
What does PEG stand for and what are its other names?
- Polyethylene glycol
- PEO (polyethylene oxide)
- POE (polyoxy ethylene)
137
What are the ways in which you can prepare ointments?
- incorporation method
| - fusion method (melt)
138
What materials can you use for the incorporation method?
- pill tile
- parchment paper
- unguator
- mortar and pestle
139
What is an unguator?
- electronic mortar and pestle
| - equipment that goes inside the ointment jar an into the machine consists of a shaft and a blade
140
Define levigation
triturating a powder in an insoluble solvent
141
What are examples of levigating agents?
- mineral oil for oil phases
| - glycerin for water phases
142
What are the steps to the incorporation method?
- incorporate drug into absorption base
| - incorporate absorption base into oleaginous base
143
What is one thing to note when mixing ingredients in the fusion method?
mix the excipients with the highest melting point first
144
What are products that you HAVE to use fusion method for?
- beeswax
- paraffin
- stearyl alcohol
- PEG with high molecular weight
145
What are things to consider when selecting the appropriate bases?
- release rate of drug from semi-solid
- desirability of topical or percutaneous drug absorption
- desirability of occulsion of moisture from the skin
- stability of drug in base
- contact time to skin
- which part of the body it's being applied to
146
What are dosage forms of semi-solids?
- ointments
- creams
- gels
- pastes
147
What does the # following PEG indicate?
the average molecular weight
148
PEG physical state with respect to molecular weight
- lower mw are liquid; higher mw are solids
- 200-600 transprent liquid
- 600-1000 semi-solid
- >1000 solid
149
What materials can you use for the fusion method?
- small sacle: porcelain dish, glass beaker
| - large sacle: large steam jacketed kettles
150
Example of USP test for semi-solids
- minimum-fill
- microbial content
- packaging
- storage
- labeling
151
Properties of ophthalmic preparations
- diameter should be < 50microm
| - sterile
152
Examples of preservatives
- paraben
- phenols
- benzoic acid
- sorbic acid
- quaternary ammonia compounds
- benzalkonium chloride
153
Properties of creams
- emulsions (usually o/w but can be w/o)
- can be easily washed off skin
- opaque
- once applied on skin, water evaporates and leaves behind a thin layer
154
Properties of gels
- aka jellies
- thixotropic
- must have gelling agent
155
Examples of gelling agents
- cabomer 940
- natural gums (tragacanth)
- cellulose derivatives ex:
- sodium carboxymethylcellulose
- HPMC
- carboxymethylcellulose
156
Properties of pastes
- must contain at least 20% of solid content
| - able to absorb serous fluid
157
What are plasters used for?
to remove corn
158
What can glycerogelatin be used for?
varicose ulcer
159
TDD
- transdermal drug delivery
- aka percutaneous absorption
- absorb into system via skin
160
scopolamine
- approved by FDA 1979
| - first TDDS approved
161
nitroglycerine
- aka trinitroglycerine
- used in angina pectoris and CHF
- releases NO (vasodilator)
162
clonidine
used for HTN
163
nicotine
used for smoking cessation
164
applications of creams
- topical skin products
| - rectal and vaginal
165
properties of jars
- clear opaque glass
| - plastic
166
properties of tubes
- aluminum
| - plastic
167
aluminum tubes
coated with epoxy resin or vinyl to eliminate any interactions between tube and content
168
plastic tubes
made of high and/or low density polyethylene
169
What is a crimping clip?
a clip to seal off the end of a metal ointment tube
170
properties of skin
- in adult, covers 2m2
- weighs 11 lbs
- receives 1/3rd of blood circulation
- avoid first pass metabolism
171
anatomy of skin
- epidermis (outer layer)
| - dermis (deeper layer)
172
properties of epidermis
- epithelial tissue
- semi-permeable membrane
- contain 90% keratinocytes and 8% melanocytes
173
properties of dermis
- strong connective tissue
| - collagen and elastic fibers
174
How does drug molecule penetrate the skin?
via passive diffusion
175
layers of epidermis
- stratum corneum
- stratum lucidum
- stratum granulosum
- stratum spinosum
- stratum germinativum / basale
176
Rotigotine
- used in parkinson
| - brand name: Neupro
177
Rivastigmine
- anticholinesterase
- used for Alzhiemers
- brand name: Exelon
178
stratum corneum
rate limiting step for drug absorption
179
subq
- hypodermis; not part of the skin
180
What are the properties that influence transdermal absorption?
- physico-chemical properties
- drug concentration
- site of absorption
- hydration status
- time of contact
- race
- individual variation: disease state, genetic, age, etc.
181
What are the types of physico-chemical properties?
- molecular weight
- solubility; part. coeff. of 1 preferred
- dissociation constant
nature of carrier
182
What are the categories of enhancers for skin absorption?
- chemical
- iontophoresis
- electroporation
- sonophoresis
183
What are other names for chemical enhancers?
- absorption promoter / enhancer
| - permeation promoter / enhance
184
chemical enhancers
- reducing resistance in s. corneum
| - causes temporary opening of tight junctions
185
What are things to consider when selecting a chemical enhancer?
- physico-chemical properties
- compatibility with formulation
- toxicity to s. corneum
186
Examples of chemical enhancers
- dimethyl sulfoxide (DMSO)
- azone
- acetone
- oleic acid
- propylene glycol
- sodium dodecyl sulfate
- sodium lauryl sulfate
187
iontophoresis
- electric current of 12-20v applied
- increase permeability of skin
- creates ion-electric field interaction -> directional force drives ion through skin
- facilitates deep penetration
188
Examples of iontophoresis
```
- lidocaine
drugs being investigated for this kind of delivery:
- dexamethason
- amino acids
- peptides
- verapamil
- propranolol
```
189
What are qualities of drugs for iontophoresis?
any drug, as long as it's ionizable
190
What can be used to treat hyperhidrosis?
- hyperhidrosis = excessive sweating
| - iontophoresis
191
electroporation
- electric current of 200-1000v applied for millisecond
- increases size of pores
- increases permeability up to four times
- has been used to deliver drugs with mw of several kDaltons
192
What is another name for electroporation?
electropermeability
193
What is another name for sonophoresis?
phonophoresis
194
sonophoresis
application of high frequency ultrasound
195
For transdermal drug delivery, what are ultrasounds used with?
coupling agent (gel, cream, etc) that transfers US energy from US transducer to skin
196
examples of drug permeation testing systems
- side-by-side diffusion cell (not used for human skin)
| - Franz diffusion cell (top-to-bottom diffusion; take gravity into account)
197
What are the components of TDDS?
- adhesive
- backing layer
- frontal layer
198
What is the backing layer made of?
Aluminum (but doesn't have to be)
199
monolithic system and examples
- drug and polymer mixed together
| - Nitro-dur, Vivelle dot, Testoderm
200
membrane-controlled system and examples
- drug and polymer are in separate compartments
- can use liquid and semi-solids
- TrasdermNitro, Transderm-Scop
201
What are the barriers to ocular drug retention?
- nascolacrimal duct
- tear turnover
- conjunctival uptake
202
What is the nasolacrimal duct?
- connection between eye and nose
| - drugs can be cleared through this
203
On average, how much fluid is there in the eye?
7-9 microL
204
How much displacement of fluid can a drop of fluid give in the eye?
- 50 microL
| - ideal is 10-15 but there isn't a dropper that can deliver that
205
List categories of ocular drugs
- anesthetics
- antibiotics
- antifungal
- anti-inflammatory
- antivirals
- astringents
- beta blockers
- miotics
- mydriatics
206
What are astringents formulations used for in the eye?
constrict blood; used in conjunctivitis
207
What are types of dosage ocular forms?
- solutions
- gel forming
- suspensions
- semi-solids
- inserts
- injections / implants
208
ocular solutions
- most common
- contains buffers, emulsifiers, preservatives, etc.
- short contact with eye
209
delivery vehicles for ocular solutions
- water
aq. mixtures of:
- lower alkanols
- vegetable oils
- polyalkylene glycols
- petrolatum based jellies
210
What are examples of in-vitro apparatuses?
- skin cadaver
- synthetic skin
- synthetic polymers
- side-by-side diffusion chain / cells
- top-to-bottom cell
211
ex-vivo
take organ out of body
212
in-situ
procedure done in localized area
213
What are advantages of transdermal delivery?
- avoids first pass metabolism
- decreased drug-food interaction
- extended therapy with single application
- increased patient compliance
214
What are disadvantages of transdermal delivery?
- only potent drugs can be used
- developments of contact dermatitis
- irritation of skin
- expensive
215
polymers (all)
- cellulose derivatives (HEC, HPMC, NaCMC)
- acrylic acid
- PVA
- combinations: PVP-ethylcellulose
- gellan
- xanthum gum
- pluronics
216
With respect to ocular solutions, how can contact time between eye and solution increase?
addition of polymers
217
ocular gel-forming solutions
- gel + polymer
- once instilled in eye, gel is formed
- enhanced retention
218
What causes the geling formation in the eye when gel-forming solutions are applied?
- pH
- tear formation
- ionic strength
- temperature
- proteins
- components of tears
219
What is the temperature for the anterior portion of the eye?
34°C
220
What are the polymers used in gel-forming solutions?
- gellan
- xanthum gum
- carbomer
- pluronic
- CAP
- methyl cellulose
221
ocular suspensions
- must be > 10 microm to decrease irritation
- longer contact time that solution
- particles retained in cul-de-sac
222
ocular semisolids
- block vision - restricted to use at bedtime
- used often in children and post-operation
- longer contact time
223
What is used as the base in ophthalmic ointments?
mineral oil; mixture of white and liquid petrolatum
224
What polymers are used to develop ophthalmic gels?
- gellan
- xanthum gum
- carbomer
- pluronic
- CAP
- methyl cellulose
225
ocular inserts
- put insert in cul de sac
| - designed to release drug slowly on zero order kinetics
226
ocular injections
- to reach posterior area
- intravitreal
- juxtascleral
- subconjunctival
- intrasclera
227
ocular implant
- planted in vitreous cavity
- releases drug over a certain period
- removed after therapy
228
What are things to consider with respect to ophthalmic preparations?
- sterility
- preservatives
- isotonicity
- buffer / pH
229
sterilization techniques
- moist heat under pressure
- dry heat
- filtration
- gas sterilization
- ionizing radiation
230
moist heat sterilization
- 121°C or 250°F
| - 15 min
231
dry heat sterilization
- 160°C or 320°F
| - 2 hours
232
filter sterilization
pores of filter are 0.2-0.7 microm
233
gas sterilization
ethylene oxide
234
preservatives for ocular drugs
- Quaternary ammonium compounds
- Oxidizing agents
- Organic mercurials
- Para-hydroxy benzoic acid esters
- Substituted alcohols and phenols
235
body's physiological tonicity
- 0.9% NaCl
- 290mOsm
- 1.9% boric acid
236
What type of solution is used to treat corneal edema?
hypertonic
237
What is normal tear fluid pH?
7. 4
| - can tolerate pH change better than we anticipate
238
What is the composition of buffers?
usually weak acid + conjugate base
239
Besides resistance in pH change, what else does buffers do?
stabilize drug
240
What are the types of contact lenses?
- hard
- soft
- rigid gas permeable
241
hard contact lenses
- not permeable
- offer clarity and crisp vision
- only cover cornea
- diameter of 7-10microm
- made of PMMA
242
soft contact lenses
- not permeable
- softer and pliable
- not as clear
- diameter of 13-15microm
- made of HEMA
243
rigid glass permeable (RGP)
- permeable
| - provide visual clarity
244
What are the types of care products for contact lenses?
- wetting solutions
- cleaning solutions
- disinfectants
- soaking and storage solutions
245
wetting solutions: contact lenses
- cellulose derivatives
- polyvinyl pyrrolidone
- polyvinyl alcohol
246
cleaning solutions: contact lenses
- surfactants
| - enzymes
247
disinfectants: contact lenses
- hydrogen peroxide
| - polyquad
248
soaking and storage solutions: contact lenses
- chlorhexidine
| - benzalkonium chloride
249
What are the types of suppositories?
- rectal
- vaginal
- urethral (less common)
250
What kind of effects are suppositories used for?
- local
| - systemic (less common)
251
properties of rectal suppositories
- adults weigh 2g, pediatrics weigh 1g
- 1.5 in long
- cylindrical
252
What are the systemic drug uses for rectal suppositories?
- sedatives
- tranquilizers
- nausea
- analgesics
253
What is another name for vaginal suppositories?
pessaries
254
properties of vaginal suppositories
- weigh 5g
- oviform of globular shaped
- sometimes needs applicator
- mostly used for local effects
255
properties of vaginal inserts
- ovoid shaped tablets
- must be administered with inserter
- disintegrated inside the vagina
256
What is another name for urethral suppositories?
bougies
257
properties of urethral suppositories
- cylindrical slender shape
- males: 5mm diam, 125mm length
- females: 5mm diam, 50mm length
- need applicator
258
What are urethral suppositories usually used for?
local anesthetic for examination
259
What are the types of suppository bases?
- cocoa butter and other fatty bases
- water-soluble or water-dispersible bases
- hydrogels
260
What are ideal properties of a suppository base?
- non-irritating to mucous membranes
- compatible with a variety of drugs
- melts, dissolves, or swells in rectal/vaginal fluids
- should not interfere with release or absorption of drug substances
261
cocoa butter and other fatty bases properties
- naturally occurring triglyceride
- melts at body temperature
- smooth; lubricant not needed
- exhibits polymorphism
262
What are substitutes to cocoa butter?
- hydrated fat
- hydrogenated regular oil
- suffer polymorph but have potential for lower rancidity
263
What are the polymorphs for cocoa butter?
- α melt at 18°C
- β melt at 37°C
- γ melt at 22°C
- melting temp. should not exceed 60°C or it will polymorph from β to α
264
What is another name for cocoa butter?
theobroma oil
265
water-soluble or water-dispersible bases properties
- dissolves / solubulizes
- offer prolonged release of drug
- can be stored at room temperature
- contain PEG or glycerinated gelatin
266
hydrogels properties
- swelling mechanism (via polymer)
| - drug comes out of polymer
267
examples of hydrogel polymers
- polyvinyl alcohol (PVA)
- hydroxyethyl methacrylate
- polyacrylic acid
- polyoxyethylene
268
What are the ways in which you can prepare suppositories?
- rolling (hand-shaping)
- compression
- molding (fusion)
269
How should glycerinated gelatin suppositories be stored?
packaged tightly closed in screw-capped containers and stored at room temperature
270
What are the uses for otic drug preparations?
- ear infections
- inflammation
- pain
- removal of cerumen
- local only; no systemic
271
What makes up the outer ear?
- pinna
- external auditory canal
- tympanic membrane
272
What makes up the middle ear?
- auditory ossicles
| - air-filled cavity in ear drum
273
What makes up the inner ear?
- chochlea
| - vestibule and semi-circular canals
274
What are formulations of otic drugs?
- solutions
- suspensions
- semi-solids
275
What is used as the traditional method to soften cerumen for removal?
- light mineral oil
- vegetable oil
- hydrogen peroxide
276
What is the active ingredient for products to soften cerumen?
cabamide peroxide which releases oxygen to disrupt integrity of impacted wax
277
What dosage forms are the only ones that you can use with controlled drug delivery (CDD)?
- tablets
| - capsules
278
What are the types of controlled drug delivery (CDD)?
XL, SR, ER, CR, PA, PL, SA, TR
279
What are CDD useful for?
to treat chronic diseases
280
What is dose dumping?
when the CDD fails and delivers the amount of drug in the tablet all at once
281
Define CDD
drug system that is capable of spatial placement and temporal release of a drug
282
What does spatial placement pertain to?
release of drug in a particular location
283
What does temporal placement pertain to?
time release of the drug
284
What are the ways in which you can maintain sustained plasma levels of the drug?
- multiple dosing
- intermittent infusion
- constant infusion
285
After how many half lives can we assume that the drug is out of the body?
- four
| - some literature use 3.3 because that equals 90%
286
intermittent infusion
drug is given continually but not continuously
287
multiple dosing
- requires strict adherence
- cannot tolerate missed doses
- if doses are missed, plasma levels not sustained and may fall below MEC
288
What is the assumption for CDD?
kinetics of drug release governs drug availability
289
What are the types of CDD systems?
- osmotically controlled
- swelling controlled
- diffusion controlled
- dissolution controlled
- ion-exchange resin
- complex formation
- magnetically controlled
- electrically controlled
290
osmotically controlled system
- has a hole in the tablet
- polymer is semi-permeable
- pH independent
291
With respect to osmotically controlled systems, what does it mean that the polymer is semi-permeable?
water and GI fluids can enter tablet but not permeable to substances coming out of tablet
292
example(s) of osmotic agents
- mannitol
| - xylitol
293
What is osmotically controlled systems dependent on?
- size of hole
- type of polymer
- type of osmotic agent / osmotic pressure
- saturated solubility of drug
294
Example(s) of semi-permeable membranes used to regulate osmotic permeation of water
- cellulose derivatives
- polyvinyl chloride
- polyvinyl alcohol
295
How does the osmotic agent play a role in osmotically controlled systems?
- osmotic agent creates a high osmotic pressure gradient inside the tablet
- fluid enters the tablet (osmosis)
- increase in volume -> drug gets pushed out of hole
296
swelling controlled system
- polymer and drug tightly packed
| - once in GIT, polymer swells to release drug
297
In a swelling controlled system, what is the release of drug dependent on?
rate of water sorption in polymer
298
Example(s) of polymers used in swelling controlled systems
- poly acrylic acid
- sodium alginate
- cellulose derivatives
299
diffusion controlled system
polymer is physical barrier to drug release
300
In a diffusion controlled system, what is the release of drug dependent on?
- nature of polymer
| - thickness of polymer
301
What are the categories of diffusion controlled systems?
- reservoir
| - matrix
302
describe the reservoir diffusion controlled systems
- drug is coated with water-insoluble polymer
- water penetrate through polymer to reach drug
- drug dissolved to produce saturated solution
- saturated solution diffuses through polymer to outside
303
If the polymer for reservoir diffusion controlled system is water-insoluble, how does the drug diffuse through it to the outside?
osmotic movement through polyemeric mesh (space between macromolecular chains)
304
For reservoir diffusion controlled systems, how can release of drug remain constant?
if concentration of drug in the core remains at saturation
305
describe the matrix diffusion controlled systems
- aka monolithic
| - drug dispersed in polymeric matrix
306
Polymers for diffusion controlled systems
- reservoir's polymers are water-INsoluble
| - matrix's can be both
307
fate of polymers for matrix diffusion controlled systems
- erode with tiem
- dissolve
- stay intact as ghost matrix
308
dissolution controlled system
dissolution of drug is the major role in drug release
309
ion exchange resin system
drug is resinated and then formulated in it's respective dosage form
310
What does it mean for a drug to be resinated?
- cationic / anionic drug passed through ion exchange resin
- cations replace H atoms
- anions replace OH atoms
- drug-resin complex = resinated
311
complex formation systems
- drug complexes which are slowly soluble in GI fluid; pH dependent
- salts of tannic acid used for this purpose
312
Characteristics of controlled release systems
- not for all drugs
- not all medical conditions need it
- dissolution and absorption release of drug should be predictable
- rate of drug release is controlled
- rate of drug release = rate of drug elimination
313
Ideal drug candidates for controlled release systems
- Absorption/elimination rate shoud not be too fast or slow
- Uniformly absorbed form the GI tract
- Effective dose should be small
- Possess good margin of safety
- Used for chronic conditions
314
Limitations of controlled release systems
- Dose dumping
- Termination of therapy is not easy
- Variable release of drug
- Absorption of released drug may not be constant
- Delayed release = delayed immediate effect of drug
315
What does modified release refer to?
drug release based on time, course, or location not offered by conventional dosage forms
316
What are the categories of modified release?
- extended release
| - delayed release
317
extended release
allows a reduction in dosing frequency
318
delayed release
releases drug at a time other than promptly after administration
319
What are repeat action tablets?
two layer tablet; one layer is IR and second layer is DR
320
What are targeted release tablets/capsules?
directed towards a target location in the GI tract
321
Can CNS drug targeting be viewed as advanced drug delivery?
Yes; needs to pass BBB
322
What are categories of nanoparticulate systems?
- nanocapsule (encapsulated drug, reservoir)
| - nanospheres (drug-polymer matrix)
323
T/F; Polymeric nanoparticles can only carry low MW substances.
False
- can deliver both low and high MW substances
- ex. genes, proteins
324
What are the advantages of nanoparticles?
- increased bioavailability
- protection from degradation
- specific targets
325
characteristics of tumor vasculature
- heterogeneous distribution
- larger in size
- high vascular density
- more permeable
- more leaky
326
What factor allows retention of NP in solid tumors?
- high vasculature
| - production of vascular mediators
327
F
- bioavailability
| - dose / AUC
328
How can you actively target a tumor?
- ligand-receptor
| - antibody-antigen
329
How are NPs utilized in targeting cancer cells?
NP conjugated with tissue or cell-specific ligand
330
examples of ligands
- lectins
- carbohydrates
- transferrin
- folate
331
passive targeting
delivering drug at local site
332
What are vectors?
gene carrier used in gene therapy
333
Steps in gene therapy
- genetic material packaged in vector to be transferred
- vector enters cytoplasm
- gene from vector to nucleus
- gene integrated into cellular DNA (if need be)
- gene expressed
334
What are the categories used in gene therapy?
- viral
| - non-viral
335
viral vectors
- part of viral genome replaced by therapeutic gene
| - this gene taken up by target cells and expressed
336
examples that viral vectors were used for
- retrovirus
- adenovirus
- adeno-associated virus
- herpes simplex virus (HSV)
337
risks of viral vectors
- inflammation
| - cellular / humoral immune response
338
What are the components of a non-viral vector?
- therapeutic gene
- gene expression system
- gene delivery system
339
plasmid-based vectors
non-viral
340
size of plasmid DNA
- huge polyanion
| - 100-200 nm
341
Plasmid potency can be reduced by which factors?
- chemical instability
- enzymatic instability
- colloidal instability
- sequestered by immune system
- uptake / adsorption of non-target cells
342
What are the most commonly used synthetic gene carrier?
- cationic polymers
| - lipids
343
What are advantages of using cationic polymers / lipids as a gene carrier?
they condense plasmids into small particles and protect them from degradation
344
Lipid-based gene delivery
- low efficiency
- pH sensitive
- fusogenic at acidic pH
- facilitate release of plasmid in endosome
345
Peptide-based gene delivery
linked macromolecules complexed into plasmids via electrostatic interaction
346
Polymer-based gene delivery
- made to interact at a more cellular / protein level
| - high specificity
347
ideal features of gene delivery system
- reach appropriate cellular target
- penetrate into target cells
- gene integrate with cell's DNA
- avoid destruction by body
348
ex-vivo: gene therapy
- take cells out of body
- cells treated in lab
- cell inserted back in body
349
in-vivo: gene therapy
- administration of vector in body
| - low integration / efficacy
350
What are the transport mechanisms for the brain endothelium to take up nutrients into CNS?
- passive diffusion
- carrier mediated
- receptor-mediated transcytosis (RMT)
351
What are substrates for RMT?
polypeptide
352
Give an example of RMT
cerebral insulin reaching the brain from circulation
353
What are the invasive CNS delivery techniques?
- intracerebroventricular drug infusion
- implants
- reversible BBB disruption
354
intracerebroventricular drug infusion
direct injection of drug into brain ventricles and large cavities in middle of the brain
355
implants( CNS delivery
implant genetically engineered cells that secrete a drug or polymeric matrix or reservoir containing drug in the brain
356
Gliadel
commercial product that is used in polymeric implant for CNS delivery
357
Reversible BBB disruption
disruption of BBB by intracarotid injection of hyperosmolar (2M) solutions of mannitolr, vasoactice substances like leukotrienes and bradykinins
358
What are the non-invasive CNS delivery techniques?
- lipidization
| - exploitation of carrier mediated system
359
lipidization
- non-invasive CNS delivery
- blocking H bond functional groups to increase lipophilicity
- binding drug to lipid moieties
- convert drug to more lipophilic prodrug
360
exploitation of carrier mediated system
- non-invasive CNS delivery
| - drug with similar molecular structure to molecules that get carried into brain via carrier
361
examples of drug that uses exploitation of carrier mediated system to get into CNS
- methyldopa
- methylparatyrosine
- phenylalanine mustard
OU Pharmaceutics
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