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111 Cards in this Set

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Draw Backs to IV drug administration
1. Reserved for
-- Critically ill patients
-- Hospitalized patients
-- Extravascular dosage forms can not be admistered

In Outpatients: ORAL dosage preferred
Terminology

Modified-release Dosage Froms
1985 - USP/NF

-Describes dosage forms that alter the timing and rate of release of the drug from the drug product

Ex:
-- Extended-release dosage forms
-- Delayed-release dosage froms
Define

Extended-Release Dosage From
-allows two fold reduction in dosing frequency

-Controlled-release products are considered extended-release dosage forms
Define

Delayed-Release Dosage From
-dont have immediate drug release. drug release in parts or times other than promptly after administration.
-Sometimes designed to have immediate drug release and than delayed release with adminstration

Ex: Enteric-coated tablets
Define

Targeted-Release Dosage From
-drug release at or near the site of action

-may have immediate or extended-release characteristics (not all are sustained release)
Define

Sustained-action release
-immediate loading dose followed by prolonged release of drug

Loading Dose + Prolonged Release

-any dosage form that provides medication over an extended time (timed release, prolonged release)
Define

Prolonged-action release
-drug release over a long period of time.

-drug release may or may not be immediate
Define

Controlled-action release
-you can tell at what which rate the drug is being released from the dosage from.

Space: Spatial - targeted to site. Time: Temporal - time controlled

-denotes that system is able to provide some actual therapeutic control (temporal nature, spatial nature, or both).
-also may be able to promote localization of drug at a active site, along with 0-order delivery.
Goals of drug delivery systems?

What roles doe modified drug delivery systems play in order to achieve the drug delivery system?
1. Deliver adequate amount of drug to site of action
-Provide and maintain: (Max therapeutic effect, max safety, max reliability)

2. with MDD system we can control: (onset, duration, intensity, elimination, distribution).
-- this allows for optimum therapeutic benefit consistent with safety and reliablity
Benefits of Modified Release Dosage Froms
- Drug levels maintained in desired range
- Side Effects minimized
-helps short half-life drugs
- enhances compliance
- lowers cost
- health care in remote areas made easier
Requirements for Modified Release Dosage froms
1. Patient monitoring (possible drug dumping)

2. Patient Education (crush or chew)
Covera HS
Verapamil

Class IV antiarrythmic drug (Calcium Channel Blocker)

-taken at bed time, stays in system over night, prevents MI due to postural hypotension
Verapamil
Cover HS

Class IV antiarrythmic drug (Calcium Channel Blocker)

-taken at bed time, stays in system over night, prevents MI due to postural hypotension
Examples of times when you dont need constant drug levels
1. Diabetes
2. Circadian rythms
-- Oral Contraceptives
-- Bronchial Dyspnea
-- COPD
-- Hypertension (Covera)
Preferred mechanism of Drug Release
1. Zero-order release

2. First-order release
**if you slow down the release of the drug, it will get close to the 0-order release**
-this works with drugs with a short therapeutic window
Two basic approaches for controlling drug availability?
1. Drug Design (takes too long, FDA approvals needed)

2. Product Design
- shorter development time &
- less money used
Terminology

used for identification in market
Sustained Release
Prolonged Release
Extended Release
Terminology

Repeat Action
stimulates sustained release
Complete the Tree


1. Diffusion Controlled
2. Dissolution Controlled
3. Osmotically Controlled
1. Diffusion Controlled
- Reservoir
- Matrix (erodible & non-erodible)

2. Dissolution controlled
- Noyes Whitney Equation
- Hixon Crowell Equation
- Single Bead vs. Multiple Beads

3. Osmotically Controlled
-Type A - Drug & Osmotic core TOGETHER
-Type B - Drug & Osmotic core SEPARATE
Complete the Tree


4. Biodegradable
5. Ion-Exchange Systems
6. Targeted Delivery Systems
4. Biodegradable
-Mechanisms I-IV
-1. Soluble; 2. Insoluble to solubline; 3. Drug trapped inside polymer; 4. Drug cleavage from polymer

5. Ion-Exchange Systems
-Penn-Kinetic System

6. Targeted Delivery Systems
-Liposomes & Nanoparticles (passive)
-Resealed Erythrocytes
-Monoclonal antibodies (active)
Define Prodrugs &
advantages of their use &
Classifications
-Latentiated form of a drug which must undergo biotransformation in vivo to become activated. NO INHERENT PHARMACOLOGICAL ACTIVITY

Advantages: improved bioavailability, patient acceptability, stability

Classes: Esters, Amides, Salts
7 Prodrug Examples
1. Pivampicillin (ampicillin) - absorption
2. L-Dopa (Dopamine)- BBB cross
3. Dipivalyl Epinephrine (Epi) - stable, 10X better F
4. Testosterone Palmitate (testosterone) - Longer DOA, better F
5. Chloramphenicol Palmitate (not bitter)
6. Clindamycin Phosphate (No IM injection irriation)
7. Erythromycin Estolate (Inc. GI tract stabilility)
Pivampicillin
Prodrug

-Ampicillin
-Better absorption of Prodrug
L-Dopa
Prodrug

-Dopamine
-Crosses BBB
Dipivalyl Epinephrine
Prodrug

-Epinephrine (ex: Propine)
-Prodrug is more stable & better bioavailability(10x)
Propine
Prodrug: Dipivalyl Epinephrine

-Epinephrine (ex: Propine)
-Prodrug is more stable & better bioavailability(10x)
Testosterone Palmitate
Prodrug

-Testosterone
-Better bioavailability & longer duration of action
Chloramphenicol Palmitate
Prodrug

-No bitterness
Clindamycin Posphate
Prodrug

-NO IM injection irritation
Erythromycin Estolate
Prodrug

-Better Stability in GI tract
Prodrug Class:

Ester Prodrug advantages
1. Better Taste
2. Increased solubility
3. Improved absorption
4. Increased oral absorption
5. Extended duration
6. Target to specific transporters
Prodrug Class:

Amide Prodrug advantages
1. Decreased GI irritation
2. Prolonged Action
Prodrug Class:

Salt Prodrug advantages
Improved Stability
List two DIFFUSION controlled delivery systems
1. Reservior systems

2. Matrix Systems
List the 4 polymers used in a Reservior system
1. Ethyl cellulose

2. EVA (ethylene-vinyl acetate copolymer)

3. Celluloses
-- HPMC (hydroxypropyl methyl cellulose)
-- PEG (Polyethylene glycol)
Define:

Microencapsulation
Process in which the small beads, used in a reservior system, are created.
Define:

Reservior System
-A core of drug (reservoir) surrounded by an inert polymeric membrane
-Any shape or size
-microencapsulation process used to create it
Reservior Systems

Mechanism of Drug release
-Diffusion controlled drug release.

-Rate of drug release is controlled by the rate of diffusion across the polymer coating
Advantages of Reservoir Systems
-Zero-order release is possible

-Release kinetics may be easily controlled by parameters
A. Polymer content (thickness)
B. Pore former in the film (diffusion coefficent)
C. Drug Load (Concentration)
D. Drug solubility (change in concentration)
Disadvantages of Reservoir System
-Lag time (freshly made)
-Burst Effect (been on shelf)

-If implanted, must be removed
-leaks are dangerous (toxic drug dumping possible)
Bayer timed-release aspirin
Reservoir System
Nitroglycerin Extended-Release capsules
Reservoir System
Nitro-bid
Reservoir System
Define:

Matrix Systems
Dissolution Controlled Delivery System

-Drug is dispensed in a solid dispersion medium which is insoluble (non-erodible) or less soluble (erodible) than the drug
Non-Erodible Matrix Systems

-Drug type to use
-5 Polymers to use
Drugs: Good for soluble drugs

Polymers
1. Waxes
2. Glycerides
3. Long chain fatty acids
4. EC (ethyl cellulose)
5. Methacrylate
Erodible Matrix Systems

-Drug type to use
-5 Polymers to use
Drug: Good for poorly soluble drugs

Polymers
1. HPMC (Hydroxypropyl methyl cellulose)
2. PEO (Polyethylene oxide) (High MW PEG)
3. HPC (Hydroxypropyl cellulose)
4. HEC (Hydroxyethyl cellulose)
5. Polyacrylic acid (Carbopol)
Matrix System

Mechanism of Drug Release
-Drug is in the exterior regions of the device is dissolved first and diffuses out of the matrix. (This process continues until the device is exhausted)
-Diffusion controlled: rate of dissolution of drug has to be much faster than rate of diffusion of drug.
Matrix Systems: Higuchi Equation

Non-porous hemogenous matrices, K (the rate constant) depends on...
M = K * t^0.5

1. Concentration of drug in the matrix
2. Diffusion coefficent in teh matrix
Matrix Systems: Higuchi Equation

Porus hemogenous matrices, K (the rate constant) depends on...
1. Porosity
2. Tortuosity
3. Solubility of the drug in the release medium
4. Diffusion coefficent in the release medium
How to you achieve constant release from matrix?
1. Have a slow release device
2. Unique geometry
3. Specific non-uniform inital concentation
4. combined diffusion/erosion/swelling mechanism
Define Graduments

Give examples

Polymers used
Non-Erodible Matrix System

-inert, insoluble or nonerodible porous plastic disc

Ex: Desoxyn (methamphetamine)
Ex: Feosol (ferrous sulfate)

Polymers: Crospovidone & Camuaba wax
Desoxyn
Non-Erodible Matrix System

Gradument - inert, insoluble or nonerodible porous plastic disc

Methamphetamine
Feosol
Non-Erodible Matrix System

Gradument - inert, insoluble or nonerodible porous plastic disc

Ferrous sulfate
Erosion Tablet
Erodible Matrix System

Constant-T (theophylline)
Constant-T
Erodible Matrix System

Erosion Tablet
(theophylline)
Uniphyl
Erodible Matrix System

(theophylline & purdue)

Polymer: Cetostearyl alcohol
LONTABS
Erodible Matrix System

Foristal: Dimethidone maleate
Procan SR tablets
Erodible Matrix System

Procainamide HCl
Novartis
SLOW-K
Erodible Matrix System

Potassium
K-TAB
Erodible Matrix System

Potassium
Name the 4 Specialized Diffusion-Controlled Systems
1. Microporus Membrane-Coated Tablets
2. Solubility-Membrane Coated Tablets
3. Modified Enteric-Coated Tablets or Beads
4. pH-Independent Release System
Explain

Microporous-Coated Tablets
Diffusion-Controlled System

-tablet of the water-soluble drug is coated with an insoluble polymer (vinyl acetate) containing a small water soluble compound (common salt)
-polymer coating contains salt which dissolves leaving pours (microscopic) in the system.
Explain

Solubility-Membrane Coated Tablets
Diffusion-Controlled System

-tables of the drug are coated with a polymer containing a plasticizer which dissolves the drug before it is release.

plasticizer - dissolves drug before release
Explain

Modified Enteric-Coated Tablets or Beads
Diffusion-Controlled System

-Tablets are coated with two polymers
1. intestinal fluid insoluble polymer (Ethyl Cellulose)
2. intestinal fluid soluble polymer (Hydroxymethyl Cellulose Phthalate)
Medrol Medules
Modified Enteric-Coated beads

-beads in a capsule
Methylpredinosolone
Explain

pH-independent release systems
Diffusion-Controlled System

-Acidic or basic drugs are mixed with appropriate buffering agents before coating with a suitable polymer

{(drug + buffer)}coating/polymer
Spansules capsules
Encapsulated Dissolution Products

-Benzedrine (amphetamine sulfate)
-Ornade (Phenypropanolamine HCl & Chloropheniramine Maleate)
Noyes-Whitney Equation
Mechanism of Drug Release in Dissolution-Controlled Devices

D = Diffusion Coefficent
S = Surface area
h = thickness
V = volume of dissolution medium
Cs = Saturation solubility of the drug in the medium
Ct = Concentration of drug in medium at time t
Hixon-Corwell Equation
Mechanism of Drug Release in Dissolution-Controlled Devices

Wo and Wt are the inital weight and the weight of the drug remaining undissolved at time t
-Plot of (Wo - W) vs t is linear

**Surface area changes related to weight changes**
Benzedrine
Encapsulated Dissolution Product
[Spansules]

(amphetamine sulfate)
-beads with different coating thicknesses of the dissolving coat that surrounds the drug
**Different coating thicknesses**
Ornade
Encapsulated Dissolution Product
[Spansules]

(phenylpropanolamine HCl & Chlorpheniramine Maleate)
-beads with different coating thicknesses of the dissolving coat that surrounds the drug
**Different coating thicknesses**
Contact Capsules
Encapsulated Dissolution Product
[other encapsulated dissolution products]

-Phenylpropanolamine HCl
-Chlorpheniramine maleate
-atropine sulfate
-scopolamine HBr
-Hyoscyamine sulfate
Methyl vinyl ether
&
Maleic anhydride
Partly esterified copolymers in the Mechanism II of the bioerosion drugs (insoluble -> soluble)
Polyactic acid
polymer of the bioerodible system (Dissolves when system is implanted into the patient)
Polyactic acid
Polyphosphoric acid
Polyglycolic acid
&
(Copolymers of these)
Polymers of mechanism III of the bioerosion drugs (drug is entrapped in a polymer which undergoes hydrolytic or enzymatic cleavage)
Osmotically Controlled system:

Mechanism of drug release (equation)
dM/dt = rate of drug leaving the orifice
k' = membrane permeability coefficent
A = membrane area
h = membrane thickness
Delta Pi = osmotic pressure differences
delta P = hydrostatic pressure difference
Cs = concentration of drug in solution

Delta P & Cs are assumed to be neglegable
Procardia X
Osmotically Controlled System

(Nifedipine)
hypertesion
Glucotrol XL
Osmotically Controlled System

(Glipizide)
Type II diabetes
Concerta
Osmotically Controlled System

(Methylphenidate)
ADHD
Tussionex suspension
Ion-Exchange Principle

-Hydrocodone & Chlorpheniramine do ion-exchange complex with polystyrene resin
Explain


Pennkinetic Drug Delivery System
2nd generation Ion-exchange principle

-Polymer and Coating membrane: Provides Rate limiting step for the diffusion of ions going through
Paul Ehrlich
"Magic Bullet" term

Selective drug targeting to Physiological sites
-organs
-tissues
-cells
-sub-cellular organelles
Targeted Drug Delivery

Passive Targeting vs. Active Targeting
Passive (physicochemical interactions) [liposomes]
-Hydrophobic
-Electrostatic
-Mass

Active Targeting (Biological specific interactions)
-antigen-antibody
-ligand-receptor
Epoietin
Epogen
Amgen
Active targeted drug delivery (biological specific interactions)
3 types of passive targeting drug veichles
1. Liposome
2. Micelle
3. Nanopartical
MLV
SUV
LUV
MLV = multilamellar vessicles = liposomes
1000-5000 nm

SUV = smal unilamellar vesicles
-Sonication of MLV leads to production of SUV
-20-80 nm

LUV = Large unilamellar vesicles
-formed by evaporation under reduced pressure
-100-1000 nm
How can you alter the permeability of liposomes
-heat
-pH
-ionic strength
-additives (cholesterol)
How do liposomes interact with cells
1. Endocytosis
2. Fusion
3. Adsorption (contents diffuse through)
Potential Advantages of Liosomes as a Drug Delivery System
-Non-immunogenic
-Protect person from potential side effects / toxicity
-Protect cargo en route to target cell
-Deliver cargo to specific cell by using binding moiety

-target organell delivery of drug (pH changes from outside, inside and nucleous of cell)
Doxorubicin HCl
Liposome DDS

-MPEG steath liposome technology
-Drug in aqueous core
-30 minute infusion with 3 week washout period
Nanoparticle matrix material
-gelatin
-albumin
-polyactic acid
-polygalactic acid
Critical micelle concentration
-the at which the concentration amphiphilic molecules form micelles
Advantages of Micelle
Versatile carrier; small size (<100); evade phagocytic macrophages; increased circulation time, bioavailability; ease of formulation (good on paper); increased solubility of poorly soluble drugs (acts like surfactants); enhance penetration of drug through cell membrane;
Passive accumulation in regions of leaky vasculature; protection from possible inactivation' prevent undesirable side-effects of cytotoxic drugs
Virosomes
liposomes with viral proteins in their membranes
Immunoliposomes
liposomes with moieties such as
-carbohydrates
-hormones
-glycoproteins

moieties (functional group or part of a molecule)
Things on "Active" liposome particles (5)
1. Antibiotics
2. Carbohydrates
3. Peptides
4. Receptors
5. Oligonucleotides
Herceptin
Monoclonal antibody drugs

-breast cancer drug
Methotrexate
Drug linked to high molecular weight occuring substance
Albumin
Dextran
Drug linked to high molecular weight occuring substance

Polysaccharides
(daunomycin)
Daunomycin
Drug linked to high molecular weight occuring substance

Polysaccharides
(Dextran)
Adriamycin
Drug linked to high molecular weight occuring substance

DNA
Albumin
Drug linked to high molecular weight occuring substance

-Protein
-MW 69kDa
-widely distributed in the body
Glycoproteins
Drug linked to high molecular weight occuring substance

-Not specific, but may be modified to have site specificity
Lipoproteins
Drug linked to high molecular weight occuring substance

-Involved in lipid distribution

HDL 300-600 kDa
LDL 230kDa
VLDL 1 million Da
Chylomicrons 1 billion Da
Ocusert
Ocular Delivery System

(pilocarpine)
-two release rates: 20 or 40 mcg/hr
-reservoir system
-Titanium dioxide: visualization of device
-Membrane: EVA (ethylene-vinyl acetate copolymer)
-Plastasizer: 2-ethyl hexyl phthalate (improves membrane permeability to release pilocarpine)
pilocarpine
Ocular Delivery System

(Ocusert)
-two release rates: 20 or 40 mcg/hr
-reservoir system

-Titanium dioxide: visualization of device
-Membrane: EVA (ethylene-vinyl acetate copolymer)
-Plastasizer: 2-ethyl hexyl phthalate (improves membrane permeability to release pilocarpine)
Progestasert
Intravaginal system

-delivers progesterone to the intra-uterine region at a rate of 65 mcg/day for 1 year
Tantum-T
Intravaginal system

-copper wire wrapped around polypropylene base.
-copper is released by a combination of:
-chelation & ionization over 40 months
CU-7
Intravaginal system

-copper wire wrapped around polypropylene base.
-copper is released by a combination of:
-chelation & ionization over 40 months
Polymers for Injections & Implants
1. Hydrogels
2. Silicones
3. Biodegradable polymers
4. Titanium based devices
Infusaid
Implantable pump

-2 compartments: Drug & Propellant

-release drug independently of the drug's properties
-can release drug directly into blood
-can be refillable
-needs implantation