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111 Cards in this Set
- Front
- Back
Draw Backs to IV drug administration
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1. Reserved for
-- Critically ill patients -- Hospitalized patients -- Extravascular dosage forms can not be admistered In Outpatients: ORAL dosage preferred |
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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 |
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Define
Extended-Release Dosage From |
-allows two fold reduction in dosing frequency
-Controlled-release products are considered extended-release dosage forms |
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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 |
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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) |
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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) |
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Define
Prolonged-action release |
-drug release over a long period of time.
-drug release may or may not be immediate |
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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. |
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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 |
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Benefits of Modified Release Dosage Froms
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- 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 |
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Requirements for Modified Release Dosage froms
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1. Patient monitoring (possible drug dumping)
2. Patient Education (crush or chew) |
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Covera HS
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Verapamil
Class IV antiarrythmic drug (Calcium Channel Blocker) -taken at bed time, stays in system over night, prevents MI due to postural hypotension |
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Verapamil
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Cover HS
Class IV antiarrythmic drug (Calcium Channel Blocker) -taken at bed time, stays in system over night, prevents MI due to postural hypotension |
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Examples of times when you dont need constant drug levels
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1. Diabetes
2. Circadian rythms -- Oral Contraceptives -- Bronchial Dyspnea -- COPD -- Hypertension (Covera) |
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Preferred mechanism of Drug Release
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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 |
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Two basic approaches for controlling drug availability?
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1. Drug Design (takes too long, FDA approvals needed)
2. Product Design - shorter development time & - less money used |
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Terminology
used for identification in market |
Sustained Release
Prolonged Release Extended Release |
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Terminology
Repeat Action |
stimulates sustained release
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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 |
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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) |
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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 |
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7 Prodrug Examples
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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) |
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Pivampicillin
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Prodrug
-Ampicillin -Better absorption of Prodrug |
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L-Dopa
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Prodrug
-Dopamine -Crosses BBB |
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Dipivalyl Epinephrine
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Prodrug
-Epinephrine (ex: Propine) -Prodrug is more stable & better bioavailability(10x) |
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Propine
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Prodrug: Dipivalyl Epinephrine
-Epinephrine (ex: Propine) -Prodrug is more stable & better bioavailability(10x) |
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Testosterone Palmitate
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Prodrug
-Testosterone -Better bioavailability & longer duration of action |
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Chloramphenicol Palmitate
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Prodrug
-No bitterness |
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Clindamycin Posphate
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Prodrug
-NO IM injection irritation |
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Erythromycin Estolate
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Prodrug
-Better Stability in GI tract |
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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 |
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Prodrug Class:
Amide Prodrug advantages |
1. Decreased GI irritation
2. Prolonged Action |
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Prodrug Class:
Salt Prodrug advantages |
Improved Stability
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List two DIFFUSION controlled delivery systems
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1. Reservior systems
2. Matrix Systems |
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List the 4 polymers used in a Reservior system
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1. Ethyl cellulose
2. EVA (ethylene-vinyl acetate copolymer) 3. Celluloses -- HPMC (hydroxypropyl methyl cellulose) -- PEG (Polyethylene glycol) |
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Define:
Microencapsulation |
Process in which the small beads, used in a reservior system, are created.
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Define:
Reservior System |
-A core of drug (reservoir) surrounded by an inert polymeric membrane
-Any shape or size -microencapsulation process used to create it |
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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 |
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Advantages of Reservoir Systems
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-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) |
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Disadvantages of Reservoir System
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-Lag time (freshly made)
-Burst Effect (been on shelf) -If implanted, must be removed -leaks are dangerous (toxic drug dumping possible) |
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Bayer timed-release aspirin
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Reservoir System
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Nitroglycerin Extended-Release capsules
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Reservoir System
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Nitro-bid
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Reservoir System
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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 |
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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 |
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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) |
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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. |
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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 |
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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 |
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How to you achieve constant release from matrix?
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1. Have a slow release device
2. Unique geometry 3. Specific non-uniform inital concentation 4. combined diffusion/erosion/swelling mechanism |
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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 |
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Desoxyn
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Non-Erodible Matrix System
Gradument - inert, insoluble or nonerodible porous plastic disc Methamphetamine |
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Feosol
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Non-Erodible Matrix System
Gradument - inert, insoluble or nonerodible porous plastic disc Ferrous sulfate |
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Erosion Tablet
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Erodible Matrix System
Constant-T (theophylline) |
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Constant-T
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Erodible Matrix System
Erosion Tablet (theophylline) |
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Uniphyl
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Erodible Matrix System
(theophylline & purdue) Polymer: Cetostearyl alcohol |
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LONTABS
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Erodible Matrix System
Foristal: Dimethidone maleate |
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Procan SR tablets
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Erodible Matrix System
Procainamide HCl Novartis |
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SLOW-K
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Erodible Matrix System
Potassium |
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K-TAB
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Erodible Matrix System
Potassium |
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Name the 4 Specialized Diffusion-Controlled Systems
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1. Microporus Membrane-Coated Tablets
2. Solubility-Membrane Coated Tablets 3. Modified Enteric-Coated Tablets or Beads 4. pH-Independent Release System |
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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. |
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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 |
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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) |
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Medrol Medules
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Modified Enteric-Coated beads
-beads in a capsule Methylpredinosolone |
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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 |
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Spansules capsules
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Encapsulated Dissolution Products
-Benzedrine (amphetamine sulfate) -Ornade (Phenypropanolamine HCl & Chloropheniramine Maleate) |
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Noyes-Whitney Equation
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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 |
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Hixon-Corwell Equation
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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** |
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Benzedrine
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Encapsulated Dissolution Product
[Spansules] (amphetamine sulfate) -beads with different coating thicknesses of the dissolving coat that surrounds the drug **Different coating thicknesses** |
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Ornade
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Encapsulated Dissolution Product
[Spansules] (phenylpropanolamine HCl & Chlorpheniramine Maleate) -beads with different coating thicknesses of the dissolving coat that surrounds the drug **Different coating thicknesses** |
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Contact Capsules
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Encapsulated Dissolution Product
[other encapsulated dissolution products] -Phenylpropanolamine HCl -Chlorpheniramine maleate -atropine sulfate -scopolamine HBr -Hyoscyamine sulfate |
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Methyl vinyl ether
& Maleic anhydride |
Partly esterified copolymers in the Mechanism II of the bioerosion drugs (insoluble -> soluble)
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Polyactic acid
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polymer of the bioerodible system (Dissolves when system is implanted into the patient)
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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)
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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 |
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Procardia X
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Osmotically Controlled System
(Nifedipine) hypertesion |
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Glucotrol XL
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Osmotically Controlled System
(Glipizide) Type II diabetes |
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Concerta
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Osmotically Controlled System
(Methylphenidate) ADHD |
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Tussionex suspension
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Ion-Exchange Principle
-Hydrocodone & Chlorpheniramine do ion-exchange complex with polystyrene resin |
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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 |
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Paul Ehrlich
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"Magic Bullet" term
Selective drug targeting to Physiological sites -organs -tissues -cells -sub-cellular organelles |
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Targeted Drug Delivery
Passive Targeting vs. Active Targeting |
Passive (physicochemical interactions) [liposomes]
-Hydrophobic -Electrostatic -Mass Active Targeting (Biological specific interactions) -antigen-antibody -ligand-receptor |
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Epoietin
Epogen Amgen |
Active targeted drug delivery (biological specific interactions)
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3 types of passive targeting drug veichles
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1. Liposome
2. Micelle 3. Nanopartical |
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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 |
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How can you alter the permeability of liposomes
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-heat
-pH -ionic strength -additives (cholesterol) |
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How do liposomes interact with cells
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1. Endocytosis
2. Fusion 3. Adsorption (contents diffuse through) |
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Potential Advantages of Liosomes as a Drug Delivery System
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-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) |
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Doxorubicin HCl
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Liposome DDS
-MPEG steath liposome technology -Drug in aqueous core -30 minute infusion with 3 week washout period |
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Nanoparticle matrix material
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-gelatin
-albumin -polyactic acid -polygalactic acid |
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Critical micelle concentration
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-the at which the concentration amphiphilic molecules form micelles
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Advantages of Micelle
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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 |
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Virosomes
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liposomes with viral proteins in their membranes
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Immunoliposomes
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liposomes with moieties such as
-carbohydrates -hormones -glycoproteins moieties (functional group or part of a molecule) |
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Things on "Active" liposome particles (5)
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1. Antibiotics
2. Carbohydrates 3. Peptides 4. Receptors 5. Oligonucleotides |
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Herceptin
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Monoclonal antibody drugs
-breast cancer drug |
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Methotrexate
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Drug linked to high molecular weight occuring substance
Albumin |
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Dextran
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Drug linked to high molecular weight occuring substance
Polysaccharides (daunomycin) |
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Daunomycin
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Drug linked to high molecular weight occuring substance
Polysaccharides (Dextran) |
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Adriamycin
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Drug linked to high molecular weight occuring substance
DNA |
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Albumin
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Drug linked to high molecular weight occuring substance
-Protein -MW 69kDa -widely distributed in the body |
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Glycoproteins
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Drug linked to high molecular weight occuring substance
-Not specific, but may be modified to have site specificity |
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Lipoproteins
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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 |
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Ocusert
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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) |
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pilocarpine
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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) |
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Progestasert
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Intravaginal system
-delivers progesterone to the intra-uterine region at a rate of 65 mcg/day for 1 year |
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Tantum-T
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Intravaginal system
-copper wire wrapped around polypropylene base. -copper is released by a combination of: -chelation & ionization over 40 months |
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CU-7
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Intravaginal system
-copper wire wrapped around polypropylene base. -copper is released by a combination of: -chelation & ionization over 40 months |
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Polymers for Injections & Implants
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1. Hydrogels
2. Silicones 3. Biodegradable polymers 4. Titanium based devices |
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Infusaid
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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 |