Lecture 14 (Cut off for Exam 4) Flashcards
Modified Release
Extended Release
Slow release of drug over extended period of time (slow or sustained release)
Targetted Release
- Enteric/colonic delivery
- Gastroretentive systems (stays in stomach and releases from there)
- Taste masking
Therapeutic Window
Concentration of plasma between the minimum effective and minimum toxic concentration
Immediate Release
- Rapid release
- High peak concentration
- Short time in the therapeutic window
- Less time in therapeutic window leads to more frequent dosing
Sustained Release
- Slower onset
- Lower peak concentration
- Longer time in the therapeutic window
- Lower peak concentration leads to less dose-dependent side effects
Delayed Release
- Same aspects as immediate release but initial release is delayed
- Released AFTER leaving stomach
Sustained-Release Advantages (4)
- Enhanced patient compliance/convenience (decreased dosing frequency)
- Reduction in blood level fluctuations
- Reduction in adverse effects
- Reduction in healthcare costs
Sustained-Release Disadvantages (3)
- Potential for dose dumping - larger quantity in one dosage unit, releasing all at once has potential for toxicity/overdose
- Requires more formulation skills
- More expensive to produce
Drug Restrictions for Sustained Release (5)
- Should exhibit neither fast or slow absorption or excretion
- Should be uniformly absorbed from GI Tract
- Administered in relative small doses
- Should possess good margin of safety (wide therapeutic window)
- Used in treatment of chronic conditions over acute
Methods to Achieve Sustained-Release (6)
- Film coating
- Osmotic Pump
- Eroding Matrices
- Microencapsulation
- Ion-exchange resins
- Inert plastic matrices
Selecting Method of SR
- Based on desired release profile
- Physio-chemical properties of API
- Available equipment, expertise, and patient issues
Reasons to Coat Drugs (6)
- Improve aesthetic appearance
- Mask taste or odor
- Prevent inadvertent contact with active
- Facilitate swallowing
- Protection from decomposition in air/humidity
- Alter release characteristics (depends on coating solubility)
Are sugar coatings utilized in controlled drug release?
No.
Sugar-Coating Advantages (4)
- Protection from atmospheric oxygen and moisture
- Masks taste and odor
- Enhances attractiveness
- Reduces dust
Sugar-Coating Disadvantages (3)
- Extensive time to apply
- “Art” & “Science”
- Increase in size and weight of tablet
Sugar-Coating Process
- Waterproofing and Sealing
- Subcoating
- Smoothing and Final Rounding
- Finishing and Coloring
- Polishing
-Similar process to candy coating. Same type of equipment and coating core
Waterproofing and Sealing
Shellac or other agent in alcohol solution utilized
Subcoating
- 3-5 coats of sugar based syrup in PVP or gelatin
- Sprinkle with dusting powder
Smoothing & Final Rounding
- 5-10 coats of thick syrup
- Dusing powder may or may not be used
Finishing & Coloring
Several coats of thin syrup
Polishing
Utilize wax-lined pans (carnuba and/or beeswax)
Gelatin-Coated
-Layer of gelatin surrounding tablet core
Applied by:
- Dipping Technique - each side dipped
- Enrobing Technique - similar to SGC process
Gelatin-Coated Advantages (4)
- Taste/odor masking
- Easier to swallow - gelatin itself helps and can compress more as a tablet than in a capsule
- Protect from light and oxygen (not water)
- Tamper resistant
Gelatin-Coated Disadvantages (2)
- Same concerns with capsules - control water and humidity
- Can’t use for controlled release
Polymer Coated Solids
- Think polymeric films surrounding a solid core
- Solid core can be tablets, pellets, beads, granules, powders
Polymer Coated Advantages (3)
- *Compared to Sugar Coatings**
- Can be used to alter release (depending on coating’s aqueous solubility)
- No significant increase in size or weight of tablet
- Faster and easier to apply
Polymer Coated Formulations
- Polymer - cellulose and acrylic
- Plasticizer - flexibility and decreases cracking
- Solvent - water or organic
- Optional Additives - Anti-sticking agents (during coating/storage), surfactant (increases spreadability), colorants/opacifiers (dyes, lakes, iron oxides), flavors and sweeteners.
Water Soluble Polymers
- Protects drug from atmospheric oxygen and moisture
- Protect from light if opacifiers included
- Masks taste and/or odor
- Improves appearance
Not used for altering drug release
Water Insoluble Polymers
- Allows for slow release of drug
- Drug slowly diffuses through film
- Aqueous solubility of API and the thickness of film influences the release rate
EX: Ethyl cellulose, Eudragit RS 30 D
Polymer Drug Release Mechanism
- Coating hydrates and swells
- Water penetrates coating and dissolves the drug
- Drug diffuses out
Thickness of Film + Release Rate
Thicker films cause increased tortuous diffusion path and slows the release of the drug.
pH-Dependent Solubility
- Delays drug release until after product passes the stomach
- Small intestine and colon are the targets
- Mechanism - ionizable functional groups that only are soluble at higher pH
- Ex: CAP, PVAP, Eudragit L
Reasons to Use Enteric Coatings (4)
- Acid Liable Drugs
- Targetting small intestine or colon
- Drug irritates stomach mucosa
- Drug degrades by gastric enzymes
Enteric Coating Drug Release Mechanism
- Coating DOESN’T stay intact
- At lower pH, the coating dissolves and the drug is released to enter solution
Reverse Enteric System
- Another example of a pH-Dependent Solubility
- Form of delayed release, but only delays in mouth
- Ionizable groups that dissolve at low pH of the stomach but not the higher pH of saliva
- Taste-masking applications
Equipment Used for Coating (3)
- Conventional coating pans - used for tablets, are like sugar coating
- Perforated coating pans - used for tablets, more efficient solvent evaporation then conventional
- Fluidized Bed Apparatus (with Wurster insert) - “popcorn” machine, used for beads, pellets, and granules
Similarities between Coating Equipment
- Atomization of polymer liquid (solution or suspension)
- Heat to evaporate solvent (water or organic)
- Movement of substrate
Coating Process
- Coating formulation (liquid) is sprayed
- Comes into contact with substrate and spreads
- Solvent evaporates
- Coalescence and polymer chains intertwine
Coated Beads/Granules/Pellets Uses
- Filled into capsules (Prilosec, Eryc)
- Compressed into tablets (PCE) - coated particles need to stay intact, the compression pressure shouldn’t fracture them
- Combine uncoated and coated particles (IR+SR)
Non-Pareil Beads
- Have a polymer layer and a rate controlling layer on top
- Think of a peanut M&M for structure
- Alternative to wet granulation
- Use a water soluble polymer
Film Coating Problems (5)
- Edgewear
- Orange Peel
- Sticking
- Picking and cratering
- Bridging of imprinted design on tablet
Gelatin Coating Application Problems
- Gelatin softens during spraying process
- Shell becomes brittle due to water evaporation
- Problems with adhesion
Hard Shell Capsule Problem
Separation of cap and body
SGC Problem
Stability issues stemming from dynamic nature of capsule.
OxyContin
- Film-coated
- Slowly releases over 12 hours when swallowed whole
- When crushed, dose dumping, a “high”, and fatal overdosing can occur
How to Decrease OxyContin Abuse
- Include sequestered antagonist in tablet so when they are crushed the antagonist is released along with the active ingredient
- When swallowed whole the sequestered antagonist wouldn’t be released
Other Abuse Determinants
- Viscosity Modifiers - not syringable (decreases dissolution)
- High melting points - resists heat and injection
- Taste modifiers - reduces snorting
- Waxy excipients - decreases snorting and makes more crush resistant
Arthrotec
- Example of a multiple layer drug
- Combination of Misoprostol and Diclofenac
- 1st Layer = Misoprostol, IR and outer soluble coating
- 2nd Layer = Diclofenac, DR and tablet core with EC
Dry Powder Coating
- Currently under investigation
- Polymers applied as powders rather than solution or suspension
- Eliminates potential interactions between substrate and coating (ex: migration of active into coating). No water used so can coat water sensitive products too
- Eliminates pollution, explosion, and toxicity with organic solutions
Electrostatic Coating
- Example of dry powder coating
- Unique and precise coating - thickness and different polymers on different parts of the tablet
- Continuous process
Osmotic Pump
-Used for SR
Structure
-Bilayer tablet core with a drug and “push” layer
-Semipermeable membrane (polymer) with a small hole
-Push layer expands to moisture as water enter through membrane, this pushes drug solution out of hole into body from increased osmotic pressure
-Creates a more stead, sustained release throughout the day
-“Snickers” structure
Example: Ditropan XL, Procardia XL, Glucotrol XL
Osmotic Pump + EC
- Example = Covera HS
- ER Verapamil HCl osmotic pump overcoated with EC
- Taken at bedtime to get a morning surge release of drug
Eroding Matrix
- Hydrophilic matrix tablets
- Drug mixed with polymer(s) and compressed into tablets
- Dry polymer hydrates to form an outer “gel” layer
- Drug releases by diffusion through gel layer OR erosion of gel layer depending on the drug solubility
- Examples: Slow-K, Sinemet CR
Microencapsulation
-Can be used to modify release
Types:
-Microencapsule - reservoir, “regular M&M” structure
-Microsphere - Matrix, “Krackel” bar structure
- Particle size is micron (VERY small)
- Filled into capsules, compressed into tablets, suspended in liquids
Wall/Matrix Materials
-Dictates release properties
Examples
- Gelatin - first used to create carbonless carbon paper
- Synthetic polymers - ethylcellulose
- Biodegrabable Polymers - polylactic and glycolic acid
**Numerous processes used to create particles
Xtampza ER
- Oxycodone ER capsule with microspheres
- Microspheres have ER and substance abuse deterrent properties
Ion-Exchange Resin
-Used for MR or taste masking
-Cationic drug complexed into anionic resins or anionic drug complexed into cationic resins
-Resin is insoluble and porous
-Drug-resin complex formed when equilibriated with drug solution
-Can be tableted, encapsulated, suspended in aqueous solution
Examples: Tussionex, Ionamin, Delsym
Ion-Exchange Resin
- Drug attached to resin
- After ingestion, an anion or cation replaces the drug on the resin (which it is depends on the charge of the drug)
Inert Plastic Matrix
-Non-eroding, used for SR
-“Krackel” bar structure before ingestion and swiss cheese structure after ingestion
-Drug granulated with inert plastic matrix (polyethylene, polyvinyl acetate)
Examples: Desoxyn Gradumet Tablets
Inert Plastic Matrix Mechanisms (3)
- Drug on surface dissolves
- Body fluids create pores of channels
- Drug leaches out in body fluids
Hot Melt Extrusion
- Used for SR
- Matrix where drug dissolved/suspended in low melting carrier
- Achieve SR by selecting appropriate carrier - wax matrix or suitable polymer
Gastric Retentive Systems (6)
- Floating - low density, CO2 production
- Sinking
- Bioadhesion
- Swelling
- Expanding
- Magnetic
All used for SR
Are SR systems good to use with drugs with narrow windows of absorption?
No, conventional SR systems are ineffective with these drug types.
Colon Drug Delivery
-Drug release controlled for local effects
-Treat specific disease states like IBS, Crohn’s Disease, and Ulcerative Colitis
-No substantial absorption
Example: Pulsin Capsule - EC and capsule dissolved in small intestine and hydrogel plug swells and ejects to release drug in colon
Rupture-Type
- Creates a “lag” time to target colon
- Comprised of drug core, swellable coating, and insoluble/permeable coating
- Mechanism: water diffusion causes inner coating to swell and the increase pressure causes the outer, insoluble coating to rupture
Rupture-Type
- Creates a “lag” time to target colon, controlled by permeability and mechanism properties of coatings
- Comprised of drug core, swellable coating, and insoluble/permeable coating
- Mechanism: water diffusion causes inner coating to swell and the increase pressure causes the outer, insoluble coating to rupture
CODES
- Example of drug exploiting natural bacteria in colon to trigger release
- EC dissolves in stomach, acid soluble/slightly permeable coating goes through small intestine
- Dissolution and release of polysaccharides in colon then allows bacteria to feed on polysaccharides and drop the pH to cause the drug to release
In-Vitro Tests
- Dissolution
- Disintegration - basket, paddle, Method III (reciprocating cylinder)
In-Vitro for Micro-flora Medications
- More challenging tests
- Use of animal caecal contents - diluted to pH of 7
- Stimulated human intestinal microbial ecosystem (SHIME) - incubation of delivery system with bacteria common to colon
- Provide some indication of in vitro performance
Enteric/Colonic/Gastroretentive In Vitro Tests
- Human and animal studies
- Pharmacokinetics (drug levels in blood)
- Gamma imaging - non-invasive imaging when drug is labeled with gamma-emitting isotope. Allows for real-time GI observations with gamma camera to visualize the disintegration of the product
Repeat Action Forms
- Behaves like 2 doses of drug from 1 tablet
- Initial drug release from tablet shell and the second dose from the inner core of tablet
- Barrier coating between the two layers
- Graph looks like two IR doses release over time
- Example: Repetabs
Repeat Action Drug Requirements
- Low dosage
- Treat chronic conditions
- Regular absorption patterns
- Fairly rapid absorption and excretion
Dosage Forms to NOT Chew
- Sublingual
- Buccal
- Enteric coatings
- Extended Release
- Products with carcinogenic release
What controls Osmotic Pump drug release? (3)
- Size of Hole
- Thickness and nature of coatings
- Surface Area